Compounds for use in the treatment of mycobacterial infections

ABSTRACT

The present invention concerns compounds of general formula (I): 
                         
in which Y and Z are chosen from CH and N; T is chosen from CO or SO 2 ; n is 1 to 3; R1 represents a group chosen, for example, from C1-C3 alkyl chains unsubstituted or substituted by fluorine, the unsubstituted or substituted cyclic, cyano, azido, alkoxy and phenyl groups; and R is chosen from the azido, cyano, alkinyl and 2-benzothiazolyl groups and an optionally substituted aromatic heterocycle with five vertices; and the use thereof in the treatment of bacterial and mycobacterial infections such as, for example, tuberculosis, leprosy and atypical mycobacterial infections. The present invention also concerns pharmaceutical compositions comprising, as the active ingredient, at least one of the abovementioned compounds and optionally an antibiotic activatable via the EthA pathway.

The present invention concerns compounds for their use in the treatmentof bacterial and mycobacterial infections such as, for example,tuberculosis, leprosy and atypical mycobacterial infections.

The present invention also concerns new compounds that can be used asmedicament in particular in the treatment of bacterial and mycobacterialinfections such as, for example, tuberculosis, leprosy and atypicalmycobacterial infections.

The present invention also concerns pharmaceutical compositionscomprising, as the active ingredient, at least one of the abovementionedcompounds and optionally an antibiotic activatable via the EthA pathway.

The present invention also concerns products (kits) containing at leastone of the aforementioned compounds and at least one antibioticactivatable via the EthA pathway as combination products for usesimultaneously, separately or spread out in time, in the therapy oftuberculosis leprosy or general mycobacterial infections.

Tuberculosis kills 2 million people every year in the world. The AIDSepidemics and the emergence of strains that are multi-resistant toantibiotics contribute to exacerbating the impact of this illness,considered by the World Health Organization as responsible for anincreasingly dangerous worldwide epidemic and as a health emergency on aglobal scale.

An increasing number of Mycobacterium tuberculosis strains ischaracterized nowadays by multi-resistance to first-line antibioticssuch as isoniazid (INH) and rifampicin (RIF). These antibiotics have ahigh therapeutic index (the therapeutic index of an active ingredient isthe ratio of therapeutic dose to toxic dose) and must thus be replacedby second-line antibiotics such as ethionamide (ETH) to which thestrains are not resistant but which have the disadvantage of having alower therapeutic index.

One strategy consisting in increasing the activity of ethionamide (ETH)by associating it to a specific compound has already been considered. Infact, ETH is a prodrug that is transformed in vivo into atherapeutically active form by the EthA enzyme (see the article“Activation of the prodrug ethionamide is regulated in mycobacteria”2000 Journal of Biological Chemistry). The resistances to ETH observedarise from the fact that the transcriptional repressor EthR of M.tuberculosis controls the expression, of the EthA enzyme and restrictsor even prevents the transformation of ETH into a therapeutically activesubstance. The aforementioned strategy is based on the combination ofETH and of a compound that inhibits EthR and thus suppresses the controlof M. tuberculosis over EthA. Thus, the document “Ethionamide BoostersCombining Bioisosteric Replacement and Structure-Based Drug Design toSolve Pharmacokinetic Issues in a series of potent 1,2,4-Oxadiazole EthRInhibitors”, published in 2012 in the Journal of Medicinal Chemistry,discloses compounds likely to potentiate the efficiency of ethionamideby inhibiting EthR of M. tuberculosis.

One aim of the present invention is to propose new compounds likely topotentiate the activity of antibiotics activatable via the EthA pathway,in particular ethionamide, by inhibition of EthR.

Another aim of the present invention is to propose compounds such aspreviously mentioned that, in combination with an antibiotic activatablevia the EthA pathway, and at identical antibiotics dosage, enable agreater efficiency to be achieved or that enable the aforementionedantibiotics dosage to be reduced whilst achieving a given efficiency.

Another aim of the present invention is to propose compounds such aspreviously mentioned that are simple and inexpensive to produce.

Another aim of the present invention is to propose compounds such aspreviously mentioned that are satisfactorily soluble in a biologicfluid.

Another aim of the present invention is to propose compounds such aspreviously mentioned that are likely to be active in particular orallyand/or that cause fewer side effects.

To achieve at least one of the aforementioned aims, the presentinvention thus proposes compounds of the general formula (I):

in which

Y and Z are chosen, independently from one another, from CH and N;

T is chosen from CO or SO₂;

n is an integer greater than or equal to 1 and lower than or equal to 3;

R1 represents a group chosen from linear or branched C1-C3 alkyl chains,linear or branched and substituted C1-C3 alkyl chains, in particularlinear or branched C1-C3 alkyl chains substituted by at least onefluorine atom, C3-C6 cyclic groups, the cyano group, the azido group,C1-C3 alkoxy chains, an unsubstituted phenyl group, a phenyl groupsubstituted by one, two or three substituents chosen, independently fromone another, from linear or branched C1-C3 alkyl chains,trifluoromethyl, linear or branched C1-3 alkoxy chains, halogens (F, Cl,Br, I), 6-membered heterocycles comprising 1 or 2 nitrogen atoms in thering and aromatic 5-membered heterocycles;

R is chosen from the azido, cyano, 2-benzothiazolyl groups and thefollowing groups (R-1) to (R-10):

in which:

R2 is chosen from H, F, Cl, Br, I;

R3 is a group chosen from H, linear or branched C1-C6 alkyl chains,linear or branched C1-C6 alkyl chains substituted by at least onefluorine atom, C3-C6 cyclic groups, the cyanomethyl group, theazidomethyl group, linear or branched C1-C4 alkoxy chains, C1-C4hydroxyalkyl groups, C1-C4 alkyl methyl ester groups, C1-C4methylcarbonylamino alkyl groups, C1-C4 methylsulfone alkyl groups, theunsubstituted phenyl group, a phenyl group substituted by one, two orthree substituents chosen, independently from one another, from C1-C3alkyl chains, trifluoromethyl, C1-3 alkoxy chains, aromatic heterocyclessuch as for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, substitutedaromatic heterocycles, in particular heterocycles substituted by alinear or branched C1-C5 alkyl chain, aromatic heterocycles substitutedby at least one fluorine atom, in particular aromatic heterocyclessubstituted by one, by two or by three fluorine atoms or by a groupchosen among the following groups (II-a and II-b):

in which

R4 is a group chosen from H, linear or branched C1-C4 alkyl chains, thephenyl group, a phenyl group substituted by at least one halogen atom,in particular substituted by one halogen atom, a phenyl groupsubstituted by a linear or branched C1-C4 alkyl chain, a phenyl groupsubstituted by a linear or branched C1-C4 alkoxy chain and a phenylgroup substituted by a trifluoromethyl group;

for their use as medicament, in particular for their use in thetreatment of bacterial and mycobacterial infections, notably in thetreatment of tuberculosis, leprosy or atypical mycobacterial infections.

“C1-C4 alkyl methyl ester groups” in the sense of the present inventionis understood to mean that the alkyl radical comprises 1 to 4 carbonatoms and that the methyl radical is bonded to anyone of the groups R-1to R-10.

In the entire description of the present invention, the terms“substituted alkyl chains” represent, regardless of the number ofcarbons of the chain under consideration, alkyl chains of which at leastone hydrogen bound to a carbon atom is substituted; when the chaincomprises at least two substituents, these substituents can be bound tothe same carbon atom or to different carbon atoms.

When the substituent of the alkyl chain is explicitly indicated, thelatter's position is not limited according to the present invention.

When at least two substituents of the alkyl chain are explicitlyindicated, the latter can be bound to the same carbon or to differentcarbons.

The terms “alkoxy chains” denote all alkoxy chains comprising the numberof carbons indicated and one oxygen atom binding two carbon atoms of thechain, regardless of the latter's position.

Atypical mycobacterial infections are defined here as mycobacterialinfections caused by at least one mycobacterium other than M.Tuberculinum and in particular mycobacterial infections involving M.Kansasii.

In the entire present application, the aforementioned chains that aresubstituted by at least one halogen atom can in particular besubstituted by one halogen atom, two halogen atoms or three halogenatoms. The halogen atoms can be different from one another on a samechain. Halogenated substituents are chosen independently from oneanother. They can substitute a same carbon atom or different carbonatoms.

The present invention also concerns compounds of the general formula(II):

in which Y, Z, T, R and n are defined as previously.

The present invention also concerns compounds that correspond to thefollowing formula (III):

in which U is chosen from CH and N; and V is chosen from O or S; n, Tand R3 being such as previously defined.

The present invention also concerns compounds of the following formula(IV):

in which n, T and R3 are defined as previously.

Advantageously, T=CO and R3 is chosen from the following groups:—CH₂SO₂R′ wherein the radical R′ is a group tert-butyl, methyl,isobutyl, isopentyl, isohexyl, 4-pyridinyl and 4-pyridinyl substitutedby a linear C1-C4 alkyl chain.

Advantageously, R3 can be, whatever n and T, a 4-pyridinyl groupsubstituted by a methyl group or ethyl chain. In this case, the cycle isadvantageously substituted in position 3, i.e. in ortho positionrelative to the nitrogen atom of the pyridinyl group.

The present invention also concerns the aforementioned compounds for useas medicament, in particular for their use in the treatment of bacterialand mycobacterial infections, notably in the treatment of tuberculosis,leprosy or atypical mycobacterial infections.

The present invention also concerns a pharmaceutical compositioncomprising, as the active ingredient, at least one of the compounds aspreviously mentioned, in particular a compound of general formula (II),(Ill) or (IV) and/or at least one compound of general formula (I) aspreviously mentioned and one pharmaceutically acceptable excipient.

Within the pharmaceutical compositions according to the invention, thecompound or compounds used as active ingredient can be used in aquantity that enables unit doses comprised between 0.3 mg and 1 gapproximately to be administered. Within the pharmaceutical compositionsaccording to the invention, the antibiotic or antibiotics activatablevia the enzymatic EthA pathway, when present, are advantageously used ina quantity enabling the administration of unit doses equal to or lowerthan the doses usually recommended by the World Health Organization(WHO, Treatment of tuberculosis: Guidelines for National Programmes.2003; WHO/CDS/TB2003.313.), national or non-governmental healthorganizations or the competent pharmaceutical laboratories.

The one skilled in the art is able to choose one or severalpharmaceutically acceptable excipients depending on the route ofadministration of the pharmaceutical composition. The one skilled in theart will of course ensure in doing so that the excipient or excipientsused are compatible with the intrinsic properties attached to thecomposition according to the present invention. Furthermore, the form ofthe medicament or pharmaceutical composition (for example a solution, asuspension, an emulsion, tablets, capsules, suppositories etc.) willdepend on the chosen administration route.

Thus, in the sense of the present invention, the medicament orpharmaceutical composition can be administered by any appropriate route,for example oral, anal, local (topical for example), systemic,intravenous, intramuscular or mucosal route, or else by using a patch,or else in encapsulated form in or immobilized on liposomes,microparticles, microcapsules, associated to nanoparticles and similar.By way of non-limiting examples of excipients suitable foradministration by the oral route, one can notably cite talcum, lactose,starch and its derivatives, cellulose and its derivatives, polyethyleneglycols, acrylic acid polymers, gelatin, magnesium stearate, animal,vegetal or synthetic fats, paraffin derivatives, glycols, stabilizers,preservatives, anti-oxidants, wetting agents, anti-caking agents,dispersants, emulsifiers, taste modifying agents, penetrating agents,solubilizing agents etc. The formulation and administration techniquesfor the medicaments and pharmaceutical compositions are well known inthe art here under consideration, the one skilled in the art can notablyrefer to the work Remington's Pharmaceutical Sciences, latest edition.

The present invention also has the aim of using at least one compoundaccording to the invention for the manufacture of a medicament intendedfor the prevention and/or treatment of bacterial infections, preferablymycobacterial infections, and more, particularly of tuberculosis,leprosy or atypical mycobacterial infections.

Advantageously, the pharmaceutical composition further comprises, asactive ingredient, at least one antibiotic chosen from antibioticsactivatable via the enzymatic EthA pathway. Ethionamide, prothionamide,isoxyl and thioacetazone are examples of antibiotics activatable via theEthA pathway. However, the invention is, not limited to theseantibiotics.

The present invention also concerns a kit or product containing at leastone compound of formula (II) and/or at least one compound of generalformula (I) and at least one antibiotic chosen from antibioticsactivatable via the enzymatic EthA pathway as combination products foruse, simultaneously, separately or spread out in time, in the therapy oftuberculosis, leprosy or general mycobacterial infections.

According to the present invention, the term “treatment” designates thecurative treatment and/or prophylactic treatment of the aforementionedinfections. The term “treatment” includes all improvement of thepatient's state, in particular any diminution of the number of bacteriapresent in at least one infection site of the patient.

In the present invention, an antibiotic activatable via the EthA pathwayis defined as any substance that at least in vitro reacts with the EthAenzyme to produce a substance having antibiotic properties. The oneskilled in the art is able to determine if an antibiotic is activatableby the EthA pathway for example by applying the method described in thefollowing publication: “Activation of the prodrug ethionamide isregulated in mycobacteria” 2000, Journal of Biological Chemistry.

EXPERIMENTAL SECTION

Microwave Synthesis

Microwave synthesis was performed in a CEM Discover™ microwave oven.

Analysis by Thin-Layer Chromatography

The thin-layer chomatographies (TLC) were performed on aluminum platescovered with a layer of 0.25 mm thickness of silica gel 60 F₂₅₄ Merck.

LC-MS Analyses

The LC-MS analyses were performed on two systems:

-   -   A triple quadrupole Varian 1200 ws system. UV detection is        performed at wave lengths of 215 and 254 nm.    -   A Waters Alliance Micromass ZQ 2000 system. Detection is        performed by means of Waters 2996 diode array system.

These apparatus are equipped with a C18 TSK-gel Super ODS 2 μm (50×4.6mm) column or an XBridge C18 (Waters) 5 μm (50×4.6 mm) column. Theinjection volumes are 20 μL.

Two gradients were used

-   -   10 min: 100% H₂O/0.1% HCOOH up to 95% ACN/0.1% HCOOH in 7        minutes at a rate of 1 mL·min⁻¹.    -   5 min: 100% H₂O/0.1% HCOOH up to 95% ACN/0.1% HCOOH in 3 minutes        at a rate of 2 mL.min⁻¹.

-   Method a: Varian, gradient 10 min, column SODS

-   Method b: Waters, gradient 10 min, column SODS

-   Method c: Waters, gradient 5 min, column XBridge

-   Method d: Waters, gradient 10 min, column XBridge    NMR Analyses

Nuclear magnetic resonance spectra (NMR) were performed on a Brücker DRX300 MHz spectrometer. The chemical shifts δ are expressed in ppmrelative to TMS and the coupling constants J in Hz (Hertz). The peaksare described according to the model: δ (splitting pattern, number ofprotons per integration, J).

The following abbreviations have been used for the multiplicity of the:s=singulet, d=doublet, t=triplet, q=quadruplet, qn=quintuplet,sx=sextuplet, sp=septuplet, n=nonuplet, br=broad (large).

Purification by Chromatography on a Pre-Packed Silica Column

The chromatographies on a pre-packed silica column were performed oncolumns of the brand AIT Chromato with a grain size from 20 to 40 μm orGrace Reveleris with a grain size of 40 μm, using a Flashmart pump.

Purification by High Pressure Liquid Chromatography (HPLC)

The purifications by preparative HPLC were performed by means of aVarian ProStar apparatus using an Omnisphere 10 C₁₈ 250 mm×41.4 mmDynamax column. The gradient used starts from a mixture (20%acetonitrile/80% water/0.1% formic acid) up to a mixture (100%acetonitrile/0.1% formic acid). Detection is performed at wavelengths of215 and 254 nm.

Melting Point

The melting points of the recrystallized products were measured usingthe capillaries method, on Büchi B-540 apparatus.

Compound 13: 4-acetyl-N-isopentyl benzene sulfonamide

3 g (1 eq.) 4-acetyl benzene sulfonic acid chloride are added to asolution of 2.39 mL (1.5 eq.) 3-methyl-butylamine and 7.54 mL (5 eq.)N-methylmorpholine in 200 mL DMF on a molecular sieve. The mixture isagitated during 3 h at AT. The DMF is evaporated under reduced pressure.The residue is taken over in the ethyl acetate and then washed by meansof an aqueous solution of HCl 1N (2×) and in brine (1×). The organicphases are dried on magnesium sulfate and then concentrated underreduced pressure to yield 3.34 g (90%) of beige powder.

LC-MS: t_(R)=5.61 min (method a); m/z: [M+H]⁺=270

CCM: R_(f)=0.44 (AcOEt 3:7 petroleum ether)

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.16 (d, 2H, ³J=8.67 Hz, 9+10); 7.95 (d,2H, ³J=8.67 Hz, 7+8); 2.89 (t, 2H, ³J=7.16 Hz); 2.65 (s, 3H, 13); 1.61(n, 1H, ³J=6.72 Hz, 3); 1.32 (q, 2H, ³J=7.08 Hz, 4); 0.84 (d, 6H,³J=6.62 Hz, 1+2)

Compound 14: 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide

4.466 g (1 eq.) trimethylphenyl ammonium tribromide are added to asolution of 3.2 g (1 eq.) of 4-acetyl-N-isopentyl benzene sulfonamide(13) in 150 mL glacial acetic acid. The reaction mixture is agitatedduring 3 h at AT. The acetic acid is evaporated under reduced pressure,the yellow solid thus obtained is taken over in the ethyl acetate andthen washed using water (2×) and in brine (1×). The organic phase isdried on magnesium sulfate and then evaporated under reduced pressure toyield 4.02 g (quantitative) of a yellow oil.

LC-MS: t_(R)=6.26 min (method a); m/z: [M+H]⁺=349

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.18 (d, 2H, ³J=8.70 Hz, 7-8); 7.98 (d,2H, ³J=8.70 Hz, 9-10); 4.71 (s, 2H, 13); 2.90 (t, 2H, ³J=7.10 Hz, 5);1.62 (n, 1H, ³J=6.70 Hz, 3); 1.32 (q, 2H, ³J=6.90 Hz, 4); 0.84 (d, 6H,³J=6.60 Hz, 1+2)

Compound 6: 4-(2-methylthiazol-4-yl)-N-isopentyl benzene sulfonamide

LC-MS: t_(R)=6.4 min (method a); m/z: [M+H]⁺=325

CCM: R_(f)=0.34 (AcOEt 3:7 petroleum ether)

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.07 (d, 2H, J=8.5 Hz), 7.9 (d, 2H,J=8.5 Hz), 7.56 (s, 1H), 4.48 (t, 1H, J=5.7 Hz), 2.98 (m, 2H), 2.8 (s,3H), 1.59 (n, 1H, J=6.7 Hz), 1.13 (sextuplet, 2H, J=7.22 Hz), 0.86 (d,6H, J=6.78 Hz)

Compound 17: 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentyl benzenesulfonamide

575 mg (1 eq.) 2-cyanothioacetamide are added to a solution of 2 g (1eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (14) in 200 mL ofTHF on a molecular sieve. The reaction mixture is agitated under THFreflux during 28 h. The THF is then evaporated under reduced pressurethen the solid thus obtained is taken over in the ethyl acetate, washedusing water (2×) and then in brine (1×). The organic phase is dried onmagnesium sulfate and then evaporated under reduced pressure. The brownsolid is recrystallized in 5 mL ethanol to yield 946 mg (47%) of paleyellow powder.

LC-MS: t_(R)=5.67 min (method a); m/z: [M+H]⁺=350

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.15 (d, 2H, ³J=8.70 Hz, 9+10); 8.05 (s,1H, 13); 7.90 (d, 2H, ³J=8.70 Hz, 7+8); 4.43 (s, 1H, 15); 2.90 (t, 2H,³J=7.20 Hz, 5); 1.52-1.68 (m, 1H, 3): 1.33 (q, 2H, ³J=7.10 Hz, 4); 0.84(d, 6H, ³J=6.65 Hz, 1+2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=159.4 (14); 153.7 (12); 139.9 (11); 137.5(6); 127.2 (7+8); 126.5 (9+10); 117.0 (13); 115.9 (16); 41.0 (5); 38.1(4); 25 (3); 21.2 (1+2); 20.9 (15)

Compound 21: 2-(4-(4-(N-isopentylsulfamoyl)phenyl)thiazol-2-yl)acetamide

100 mg 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentyl benzene sulfonamide(17) are solubilized in 100 μL sulfuric acid at 96%. The solution isagitated at AT during 12 h. The reaction medium is then poured into 100μL of ammonia solution at 28% at 0° C. Ammonia is then added until a pHof 9 is reached. The solution is then filtered, the filtrate pH isneutralized with HCl 1N and then extracted using ethyl acetate. Theorganic phases are collected, dried on magnesium sulfate and thenevaporated under reduced pressure to yield 64 mg (61%) of white powder.

LC-MS: t_(R)=5.20 min (method a); m/z: [M+H]⁺=368

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.12 (d, 2H, ³J=8.61 Hz, 9+10); 7.97 (s,1H, 13); 7.89 (d, 2H, ³J=8.61 Hz, 7+8); 4.05 (s, 1H, 15); 2.90 (t, 2H,³J=7.18 Hz, 5); 1.62 (n, 1H, ³J=6.40 Hz, 3); 1.34 (q, 2H, ³J=7.08 Hz,4); 0.84 (d, 6H, ³J=6.62 Hz, 1+2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=173.2 (16); 165.9 (14); 154.4 (12); 141.2(11); 139.6 (6); 128.7 (7+8); 127.9 (9+10); 118.1 (13); 42.5 (5); 39.7(4); 26.6 (3); 22.8 (1+2)

Compound 22: 2-(4-(4-(N-isopentylsulfamoyl)phenyl)thiazol-2-yl) aceticacid

A solution of 200 mg (1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentylbenzene sulfonamide (17) in 2.5 mL water and 45.8 mg (2 eq.) NaOH isheated under reflux during 15 h. The pH is then adjusted to 4-5 at AT bymeans of a solution of glacial acetic acid. The produce is extractedusing ethyl acetate. The organic phases are collected, washed with anaqueous solution of HCl with a pH=4, dried on magnesium sulfate and thenevaporated under reduced pressure to yield 122 mg (58%) of beige powder.

LC-MS: t_(R)=5.07 min (method a); m/z: [M+H]⁺=369

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.11 (d, 2H, ³J=8.80 Hz, 9+10); 7.97 (s,1H, 13); 7.89 (d, 2H, ³J=8.80 Hz, 7+8); 2.90 (t, 2H, ³J=7.30 Hz, 5);1.61 (n, 1H, ³J=6.70 Hz, 3); 1.34 (q, 2H, ³J=7.20 Hz, 4); 0.84 (d, 6H,³J=6.60 Hz, 1+2)

General Procedure (i)

99 μL (5 eq.) N-methylmorpholine and between 1 and 1.5 eq. ofcorresponding amine are added to a solution of 50 mg (1 eq.)4-(2-methylthiazol-4-yl)benzene sulfonic acid chloride in 4 mL anhydrousDMF. The mixture is agitated at AT during 2 h. The DMF is evaporatedunder reduced pressure. The product is taken over in the ethyl acetate,washed using water (2×) and then in brine (1×). The organic phases aredried on magnesium sulfate and then evaporated under reduced pressure.

Compound 23: N-(3,3-dimethylbutyl)-4-(2-methylthiazol-4-yl)benzenesulfonamide

Procedure (i) with 38.7 μL (1.5 eq.) 3,3-dimethylbutylamine.

26.5 mg (44%) of beige powder.

LC-MS: t_(R)=6.79 min (method a); m/z: [M+H]⁺=339

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.09 (d, 2H, ³J=8.70 Hz, 10+11); 7.89(d, 2H, ³J=8.70 Hz, 8+9); 7.84 (s, 1H, 14); 2.86-2.92 (m, 2H, 6); 2.77(s, 3H, 16); 1.35-1.40 (m, 2H, 5); 0.85 (s, 9H, 1+2+3)

NMR ¹³C (DMSO-d₆, 75 MHz): δ ppm=168.7 (15); 154.4 (13); 140.9 (7);139.5 (12); 128.6 (8+9); 127.8 (10+11); 116.9 (14); 44.3 (5); 40.8 (6);30.5 (4); 29.7 (1+2+3); 18.9 (16).

Compound 24: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoropropyl)benzenesulfonamide

Procedure (i) with 26.9 mg (1 eq.) 2,2,2-trifluoropropylaminehydrochloride.

26.6 mg (39%) of beige powder.

LC-MS: t_(R)=5.80 min (method a); m/z: [M+H]⁺=351

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.10 (d, 2H, ³J=8.80 Hz, 7+8); 7.90 (d,2H, ³J=8.80 Hz, 5+6); 7.86 (s, 1H, 11); 3.12 (t, 2H, ³J=7.3) Hz, 3);2.77 (s, 3H, 13); 0.2.39 (qt, 2H, ³J₂₋₁=10.80 Hz, ³J₂₋₃=7.30 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.7 (12); 154.3 (10); 140.5 (4); 139.8(9); 128.6 (5+6); 127.9 (7+8); 127.6 (q, ¹J_(C-F)=276.1 Hz, 1); 117.1(11); 37.39 (d, ³J_(C-F)=3.10 Hz; 3); 35.21 (q, ²J_(C-F)=27.9 Hz, 2);18.9 (13).

Compound 25:4-(2-methylthiazol-4-yl)-N-(2,2,3,3,3-pentafluoropropyl)benzenesulfonamide

Procedure (i) with 38.9 μL (1 eq.) 2,2,3,3,3-pentafluoropropylamine, 100mg sulfonic acid chloride, 8 mL anhydrous DMF and 198 μLN-methylmorpholine.

40.1 mg (29%) of beige powder.

LC-MS: t_(R)=6.22 min (method a); m/z: [M+H]⁺=387

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.10 (d, 2H, ³J=8.80 Hz, 7+8); 7.91 (d,2H, ³J=8.80 Hz, 5+6); 7.86 (s, 1H, 11); 3.70 (td, 2H, ³J₃₋₂=15.80 Hz,⁴J₃₋₁=0.8 Hz, 3); 2.77 (s, 3H, 13).

Compound 26: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide

Procedure (i) with 24.4 mg (1 eq.) 2,2,2-trifluoroethylaminehydrochloride.

19.8 mg (31%) of beige powder.

LC-MS: t_(R)=5.53 min (method a); m/z: [M+H]⁺=337

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.09 (d, 2H, ³J=8.80 Hz, 6+7); 7.91 (d,2H, ³J=8.80 Hz, 4+5); 7.85 (s, 1H, 10); 3.68 (q, 2H, ³J=9.00 Hz, 2);2.80 (s, 3H, 12)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.7 (11); 154.3 (9); 141.2 (8);139.8/8); 125.0 (q. ¹J_(C-F)=277 Hz, 1); 117.1 (10); 45.06 (q,²J_(C-F)=35.0 Hz, 2); 12.9 (12).

Compound 27: 4-(2-methylthiazol-4-yl)-N-(4,4,4-trifluorobutyl)benzenesulfonamide

Procedure (i) with 55.7 mg (1.2 eq.) 4,4,4-trifluorobutylamine, 100 mgsulfonic acid chloride, 5 mL anhydrous DMF and 198 μLN-methylmorpholine.

75.1 mg (54%) of beige powder.

LC-MS: t_(R)=6.13 min (method b); m/z: [M+H]⁺=365

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.02 (d, 2H, ³J=8.74 Hz, 8+9); 7.89 (d,2H, ³J=8.74 Hz, 6+7); 7.46 (s, 1H, 12); 5.10 (t, 1H, ³J=6.39 Hz, NH);3.03 (q, 2H, ³J=6.64 Hz, 4); 2.22-2.06 (m, 2H, 2); 1.76 (qn, 2H, ³J=7.33Hz, 3)

NMR ¹³C (CDCl₃, 75 MHz): δ ppm=166.8 (13); 153.2 (11); 138.8 (10); 138.5(5); 127.6 (6+7); 127.0 (8+9); 126.9 (q, ¹J_(C-F)=276 Hz, 1); 115.2(12); 42.0 (4); 30.9 (q, ²J_(C-F)=29.0 Hz, 2); 22.6 (3); 19.4 (14).

Compound 28:N-(2,2,3,3,4,4,4-heptafluorobutyl)-4-(2-methylthiazol-4-yl)benzenesulfonamide

Procedure (i) with 29.2 μL (1.2 eq.)2,2,3,3,4,4,4-heptafluorobutylamine.

34 mg (44%) of beige powder.

LC-MS: t_(R)=6.65 min (method b); m/z: [M+H]⁺=437

NMR ¹H (CDCl₃ 300 MHz): δ ppm=8.02 (d, 2H, ³J=8.70 Hz, 8+9); 7.88 (d,2H, ³J=8.70 Hz, 6+7); 7.49 (s, 1H, 12); 5.50 (br s, 1H, NH); 3.75 (td,2H, ³J₄₋₃=15.30 Hz, ⁴J₄₋₂=5.10 Hz, 4); 2.80 (s, 3H, 14)

NMR ¹⁹F uncoupled ¹H (CDCl₃, 282 MHz): δ ppm=−127.36/−127.51 (m, 2F, 3);−118.74 (qt, 2F, ³J₂₋₁=9.30 Hz, ³J₂₋₃=5.60 Hz, 2); −80.71, (t, 3F,³J=9.30 Hz, 1).

Compound 30: 4-acetyl-N-(3,3,3-trifluoropropyl)benzene sulfonamide

754 μL (5 eq.) N-methylmorpholine and 300 mg (1 eq.) 4-acetylbenzenesulfonic acid chloride are successively added to a solution of 186 mg(1.2 eq.) 3,3,3-trifluoropropylamine hydrochloride in 10 mL anhydrousDMF. The mixture is agitated during 2 h at AT. The DMF is evaporatedunder reduced pressure. The product is taken over in the ethyl acetateand then washed by means of an aqueous solution of HCl 1N (2×) and thenin brine (1×). The organic phases are dried on magnesium sulfate andthen concentrated under reduced pressure to yield 303 mg (75%) of paleyellow powder.

LC-MS: t_(R)=5.33 min (method a); m/z: [M+H]⁺=296

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.15 (d, 2H, ³J=8.60 Hz, 7+8); 8.09 (brs, 1H, NH); 7.93 (d, 2H, ³J=8.60 Hz, 5+6); 2.99 (t, 2H, ³J=6.90 Hz, 3);2.43 (qt, 2H, ³J₂₋₁=11.22 Hz, ³J₂₋₃=6.96 Hz, 2)

Compound 31: 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide

A solution of 303 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzenesulfonamide (30) in 35 mL of glacial acetic acid is added drop by dropto a solution of 386 mg (1 eq.) trimethylphenylammonium tribromide in 30mL of glacial acetic acid. The reaction mixture is agitated during 4 hat AT. 0.1 eq. brominating reagent are added to consume completely theresidual non-brominated ketone. The acetic acid is evaporated underreduced pressure, the yellow solid thus obtained is taken over in theethyl acetate and then washed using water (2×) and in brine (1×). Theorganic phase is dried on magnesium sulfate and then evaporated underreduced pressure to yield 358 mg (93%) of beige solid.

LC-MS: t_(R)=5.85 min (method a); m/z: [M+H]⁺=372

Compound 32:4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide

105.4 mg (1.1 eq.) 2-cyanothioacetamide are added to a solution of 358mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31) in 25mL THF on a molecular sieve. The reaction mixture is left under THFreflux during 24 h. An additional 0.1 eq 2-cyanothioacetamide are added,the medium is agitated for a further 1 h at 70° C. The THF is thenevaporated under reduced pressure and then the solid thus obtained istaken over in the ethyl acetate and washed in brine (2×). The organicphase is dried on magnesium sulfate and then evaporated under reducedpressure. The olive-green oil thus obtained is agitated for 1 h at AT inmethanol in the presence of MgSO₄ and activated charcoal. The medium is,filtrated to yield a cloudy yellow filtrate. The methanol is evaporatedunder reduced pressure. The yellow solid is taken over in the ethanoland then filtrated again to yield 270 mg (75%) of yellow solid used asis in the following steps.

LC-MS: t_(R)=5.35 min (method a); m/z: [M+H]⁺=376

Compound 33:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)methylacetate

1.05 mL (36 eq.) anhydrous methanol, 1.60 mL (18 eq.) TMSCl and 270 mg(1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide (32) are successively added at AT in a dry flask and underargon. The mixture is then agitated at 50° C. during 15 h and then leftto return to AT. 1 mL water is then added and the pH is neutralized bymeans of an aqueous solution saturated with NaHCO₃. The mixture isagitated 10 min at AT and then extracted using ethyl acetate. Theorganic phases are washed in brine (2×), dried on magnesium sulfate andevaporated. The orange solid thus obtained is purified on a pre-packedsilica column (EtOAc 1:9 petroleum ether→EtOAc 3:7 petroleum ether) toyield 137 mg (47%) of pale beige powder.

LC-MS: t_(R)=6.22 min (method b); m/z: [M+H]⁺=409

NMR ¹H (CDCl₃, 300 MHz): δ ppm=8.06 (d, 2H, ³J=8.40 Hz, 7+8); 7.91 (d,2H, ³J=8.40 Hz, 5+6); 7.64 (s, 11); 4.81 (t, 1H, ³J=6.50 Hz, NH); 4.17(s, 2H, 13); 3.81 (s, 3H, 15); 3.25 (q, 2H, ³J=6.70 Hz, 3); 2.37 (qt,2H, ³J₂₋₁=10.50 Hz, ³J₂₋₃=6.80 Hz, 2)

NMR ¹³C (CDCl₃, 75 MHz): δ ppm=169.4 (14); 162.3 (12); 153.0 (10); 138.7(4 or 9); 138.5 (4 or 9); 127.6 (5+6); 127.0 (7+8); 125.9 (q,¹J_(C-F)=276.7 Hz, 1); 116.6 (11); 52.7 (15); 38.6 (13); 36.7 (3); 34.5(q, ²J_(C-F)=29.0 Hz, 2).

Compound 34:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)ethylacetate

186 μL (12 eq.) absolute ethanol, 195 μL TMSCl (6 eq.) and 100 mg (1eq.) 4-(2-(cyanonnethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide (32) are successively added at AT in a dry flask and underargon. The mixture is then agitated at 30° C. during 48 h. The nitrileis then converted to 67% in the desired ester and to 33% in carboxylicacid (HPLC analysis, 215 nm). 99 μL (3 eq.) SOCl₂ are then added in 466μL (30 eq.) absolute ethanol. The reaction medium is agitated at 40° C.during 48 h and then left to return to AT 1 mL water is then added andthe pH is neutralized by means of an aqueous solution saturated withNaHCO₃. The mixture is agitated 10 min at AT and then extracted usingethyl acetate. The organic phases are washed in brine, dried onmagnesium sulfate and evaporated. The orange solid thus obtained ispurified on a pre-packed silica column (AcOEt 1:9 petroleum ether→AcOEt3:7 petroleum ether) to yield 66 mg (59%) of pale beige powder.

LC-MS: t_(R)=6.22 min (method b); m/z: [M+H]⁺=423

NMR ¹H (CDCl₃ 300 MHz): δ ppm=8.04 (d, 2H, ³J=8.70 Hz, 7+8); 7.90 (d,2H, ³J=8.70 Hz, 5+6); 7.63 (s, 1H, 11); 5.11 (t, 1H, ³J=6.50 Hz, NH);4.27 (q, 2H, ³J=7.20 Hz, 3); 4.14 (s, 2H, 13); 3.24 (q, 2H, ³J=6.80 Hz,15); 2.36 (qt, 2H, ³J₂₋₁=10.60 Hz, ³J₂₋₃=6.90 Hz, 2); 1.33 (t, 3H,³J=7.10 Hz, 16)

NMR ¹³C (CDCl₃, 75 MHz): δ ppm=169.0 (14); 162.6 (12); 153.0 (10); 138.8(4); 128.6 (9); 127.7 (5+6); 127.1 (7+8); 126 (q, ¹J_(C-F)=276 Hz, 1);116.7 (11); 61.9 (15); 39.0 (13); 36.7 (3); 34.6 (q, ²J_(C-F)=28.3 Hz,2); 14.2 (16)

Compound 35:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)isopropyl acetate

244 μL (12 eq.) anhydrous isopropanol, 195 μL (6 eq.) TMSCl and 100 mg(1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide (32) are successively added at AT in a dry flask and underargon. The mixture is then agitated at 30° C. during 48 h. 197 μL (6eq.) SOCl₂ are then added in 466 μL (30 eq.) anhydrous isopropanol. Thereaction medium is agitated at 40° C. during 48 h and then left toreturn to AT. 1 mL water is then added and the pH is neutralized bymeans of an aqueous solution saturated with NaHCO₃. The mixture isagitated for 10 min at AT and then extracted using ethyl acetate. Theorganic phases are washed in brine (2×), dried on magnesium sulfate andevaporated. The orange solid thus obtained is purified on a pre-packedsilica column (AcOEt 1:9 petroleum ether→AcOEt 3:7 petroleum ether). Theproduct is purified a second time on HPLC to yield 29 mg (25%) of palebeige powder.

LC-MS: t_(R)=6.50 min (method b); m/z: [M+H]⁺=437

NMR ¹H(CDCl₃, 300 MHz): δ ppm=8.04 (d, 2H, ³J=8.70 Hz, 7+8); 7.90 (d,2H, ³J=8.70 Hz, 5+6); 7.63 (s, 1H, 11); 5.06-5.18 (m, 15+NH); 4.11 (s,2H, 13); 3.23 (q, 2H, ³J=6.8 Hz, 3); 2.36 (tq, 2H, ³J₂₋₁=10.60 Hz,³J₂₋₃=6.90 Hz, 2); 1.30 (d, 6H, ³J=6.30 Hz, 16+17)

NMR ¹³C (CDCl₃, 75 MHz): δ ppm=168.6 (14); 162.8 (12); 152.9 (10); 138.8(4 or 9); 138.5 (4 or 9); 127.7 (5+6); 127.1 (7+8); 125.9 (q,¹J_(C-F)=277.5 Hz, 1); 116.7 (11); 69.7 (15); 39.4 (13); 36.7 (3); 34.5(q, ²J_(C-F)=28.3 Hz, 2); 21.8 (16+17)

Compound 36:N-isopropyl-2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)acetamide

54 mg 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)methyl acetate (33) and 1 mL isopropylamine are introduced in a 5 mL dryflask. The mixture is heated under isopropylamine reflux during 5 h. Anadditional 0.5 mL isopropylamine are added and the mixture is heatedunder reflux for a further 4 h. The isopropylamine is then evaporatedunder reduced pressure. The product is taken over in ethyl acetate andwashed in brine (2×). The organic phase is dried on magnesium sulfateand then evaporated under reduced pressure. The orange solid thusobtained is purified on a pre-packed silica column (DCM 98:2 MeOH) toyield 32 mg (56%) of beige powder.

LC-MS: t_(R)=5.57 min (method b); m/z: [M+H]⁺=436

NMR ¹H DMSO-d₆ 300 MHz): δ ppm=8.22 (s, 1H, 11); 8.14 (d, 2H, ³J=8.51Hz, 7+8); 7.89 (d, 2H, ³J=8.51 Hz, 5+6); 4.07 (s, 2H, 13); 3.92-3.79 (m,1H, 15); 2.99 (t, 2H, ³J=6.91 Hz, 3); 2.43 (qt, 2H, ³J₂₋₁=11.21 Hz,³J₂₋₃=6.96 Hz, 2); 1.08 (d, 6H, ³J=6.58 Hz)

Compound 37: 5-methylhexanethioamide

2 mL 5-methylhexanoic acid and 5 mL thionyl chloride are introduced in a25 mL flask. The mixture is heated at 50° C. during 1 h and then thethionyl chloride is evaporated under reduced pressure. A mixture CH₃CN(5 mL) (10 mL) NH₄OH (28%) is then added at 0° C. The solution is thenagitated during 15 min at 0° C. The product is extracted using ethylacetate. The organic phases are collected, dried on magnesium sulfateand then evaporated under reduced pressure to yield a white powder.

2.9 g (0.5 eq.) Lawesson reagent and 50 mL anhydrous THF are then addedto the product. The solution is agitated at AT during 4 h. The THF isevaporated under reduced pressure and the product is purified on apre-packed silica column (Cyclohexane 85:15 AcOEt→Cyclohexane 80:20AcOEt) to yield 950 mg (47%) of transparent oil that then crystallizes.

LC-MS: t_(R)=3.03 min (method c); m/z: [M+H]⁺=146

NMR 1H (CDCl₃ 300 MHz): δ ppm=8.35+7.46 (NH₂); 2.58 (t, 2H, ³J=7.60 Hz,2); 1.64-1.74 (m, 2H, 3 or 4); 1.50 (sp, 1H, ³J=6.70 Hz, 5); 1.12-1.21(m, 2H, 3 or 4); 0.82 (d, 6H, ³J=6.60 Hz, 6+7)

Compound 38:4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide

232 mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31)are added to a solution of 90 mg (1 eq.) 5-methylhexanethioamide (37) in20 mL anhydrous THF. The reaction medium is heated under reflux during 3h. The THF is then evaporated under reduced pressure. The product istaken over in the ethyl acetate, washed in water (2×) and then in brine(1×). The organic phase is dried on magnesium sulfate and thenevaporated under reduced pressure. The yellow oil thus obtained ispurified on a pre-packed silica column (Cyclohexane 9:1 AcOEt 4Cyclohexane 8:2 AcOEt) to yield 60 mg (24%) of beige powder.

LC-MS: t_(R)=7.60 min (method d); m/z: [M+H]⁺=421

NMR ¹H (CDCl₃ 300 MHz): δ ppm=8.07 (d, 2H, ³J=8.60 Hz, 5+6); 7.91 (d,2H, ³J=8.60 Hz, 7+8); 7.51 (s, 1H, 11); 4.89 (t, 1H, ³J=6.50 Hz, NH);3.26 (q, 2H, ³J=6.70 Hz, 3); 3.06 (t, 2H, ³J=7.70 Hz, 13); 2.37 (qt, 2H,³J₂₋₁=10.70 Hz ³J₂₋₃=6.70 Hz, 2); 1.85 (q, 2H, ³J=7.80 Hz, 14); 1.63 (n,1H, ³J=6.70 Hz, 16); 1.30-1.38 (m, 4H, 15+fat); 0.92 (d, 6H, ³J=6.6 Hz,17+18)

NMR ¹³C (CDCl₃ 75 MHz): δ ppm=172.6 (12); 153.0 (10); 139.2 (9); 138.3(4); 127.7 (7+8); 127.2 (5+6); 120.5-131.5 (q, ¹J_(C-F)=277.2 Hz, 1);114.9 (11); 38.5 (15); 36.8 (3); 34.6 (q, ²J_(C-F)=28.4 Hz, 2); 34.0(13); 28.1 (14); 28.0 (16); 22.7 (17+18)

Compound 39:4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzenesulfonamide

150 mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31)are added to a solution of 78.3 mg (1 eq.)2-(tert-butylsulfonyl)ethanethioamide in 7 mL anhydrous THF. Thereaction medium is heated under reflux during 72 h. The THF is thenevaporated under reduced pressure. The product is taken over in theethyl acetate, washed in water and then in brine. The organic phase isdried on magnesium sulfate and then evaporated under reduced pressure.The product thus obtained is purified by HPLC to yield 119 mg (63%) ofbeige powder.

LC-MS: t_(R)=5.67 min (method d); m/z: [M+H]⁺=471

NMR ¹H DMSO-d₆ 300 MHz): δ ppm=8.44 (s, 1H, 11); 8.19 (d, 2H, ³J=8.70Hz, 7+8); 7.94 (t, 1H, ³J=6.0 Hz, NH); 7.90 (d, 2H, ³J=8.70 Hz, 5+6);5.09 (s, 2H, 13); 3.00 (q, 2H, ³J=6.60 Hz, 3); 2.44 (qt, 2H, ³J₂₋₁=11.2Hz, ³J₂₋₃=7.0 Hz, 2); 1.38 (s, 9H, 15+16+17)

NMR ¹³C DMSO-d₆ 75 Hz: δ ppm=157.1 (12); 152.5 (10); 139.0 (4); 137.4(9); 127.2 (5+6); 126.6 (7+8); 126.4 (q, ¹J_(C-F)=277.0 Hz, 1); 120.0(11); 60.2 (14); 50.3 (13); 36.03 (q, ³J_(C-F)=3.70 Hz, 3); 66.3 (q,²J_(C-F)=27.2 Hz, 2); 22.9 (15+16+17)

Compound 40: 4-iodo-N-(3,3,3-trifluoropropyl)benzene sulfonamide

1.82 mL (5 eq.) N-methylmorpholine are added to a solution of 593.2 mg(1.2 eq.) 3,3,3-trifluoropropylamine hydrochloride in 50 mL DMF. Themixture is agitated for 5 min at AT and then 1 g (1 eq.) 4-iodobenzenesulfonic acid chloride is added. The reaction medium is agitated at ATduring 2 h. The DMF is evaporated under reduced pressure and then theproduct is taken over in the ethyl acetate, washed in water (2×) and inbrine (1×). The organic phase is dried on magnesium sulfate and thenevaporated under reduced pressure to yield 1.17 g (94%) of pale yellowsolid.

LC-MS: t_(R)=6.22 min (method b); m/z: [M−H]⁻=378

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=7.96 (d, 2H, ³J=8.70 Hz, 5+6 or 7+8);7.60 (d, 2H, ³J=8.70 Hz, 5+6 or 7+8); 4.81 (m, 1H, NH); 3.25 (q, 2H,³J=6.70 Hz, 3); 2.43 (qt, 2H, ³J₂₋₁=10.60 Hz, ³J₂₋₃=6.80 Hz, 2)

Compound 41: 4-(4-methylthiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide

40.0 μL (1 eq.) 4-methylthiazole, 4.9 mg (0.05 eq.) palladium acetate,83.7 mg (1 eq.) copper iodide and 150 mg (0.9 eq.)4-iodo-N-(3,3,3-trifluoropropyl)-benzene sulfonamide (40) are placedsuccessively in a schlenk under an argon flow. 1.5 mL anhydrous DMF areadded via a cannula under argon at ambient temperature. The schlenk isdrawn three times under vacuum and filled successively with argon. Thereaction mixture is agitated at 140° C. under argon during 48 h. Thereaction medium is diluted at AT with 2 mL of a mixture of ethyl acetateand of an aqueous solution saturated with NH₄Cl (1:1 by volume). Themedium is then filtrated and the solid washed using ethyl acetate. Theorganic phase is washed in brine (2×), dried on magnesium sulfate,filtrated on celite and then evaporated under reduced pressure. Theproduct is then purified on a pre-packed silica column (AcOEt 1:9Petroleum ether→AcOEt 2:8 petroleum ether) to yield 73 mg (53%) of whitepowder.

LC-MS: t_(R)=6.07 min (method b); m/z: [M+H]⁺=351

NMR ¹H (CD₂Cl 300 MHz): δ ppm=8.11 (d, 2H, ³J=8.70 Hz, 7+8); 7.91 (d,2H, ³J=8.70 Hz, 5+6); 7.04 (s, 1H, 11); 4.83 (m, 1H, NH); 3.26 (q,³J=6.70 Hz, 3); 2.51 (s, 3H, 13); 2.39 (tq, 2H, ³J₂₋₁=10.60 Hz,³J₂₋₃=6.80 Hz, 2)

NMR ¹³C (CD₂Cl₂ 75 MHz): δ ppm=164.8 (10); 154.4 (12); 141.0 (4); 137.0(9); 128.0 (5+6); 127.2 (7+8); 126.85 (q, ¹J_(C-F)=277.1 Hz, 1); 116.9(11); 36.4 (q, ³J_(C-F)=3.8 Hz, 3); 33.6 (q, ²J_(C-F)=27.4 Hz, 2); 17.3(13)

Compound 42: 4-(benzo[d]thiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide

48.0 μL (1 eq.) 4-methylthiazole, 4.9 mg (0.05 eq.) palladium acetate,83.7 mg (1 eq.) copper iodide and 150 mg (0.9 eq.)4-iodo-N-(3,3,3-trifluoropropyl)-benzene sulfonamide (40) aresuccessively placed in a schlenk under an argon flow. 1.5 mL anhydrousDMF are added via a cannula under argon at ambient temperature. Theschlenk is drawn three times under vacuum and filled successively withargon. The reaction mixture is agitated at 140° C. under argon during 48h. The reaction medium is diluted at AT with 2 mL of a mixture of ethylacetate and of an aqueous solution saturated with NH₄Cl (1:1 by volume).The medium is then filtrated and the solid washed using ethyl acetate.The organic phase is washed in brine (2×), dried on magnesium sulfate,filtrated on celite and then evaporated under reduced pressure Theproduct is then purified on a pre-packed silica column (AcOEt 1:9petroleum ether→AcOEt 2:8 petroleum ether). The product is thenrecrystallized in 2 mL ethanol to yield 31 mg (20%) of transparentcrystals.

LC-MS: t_(R)=6.73 min (method b); m/z: [M+H]⁺=387

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.34 (d, 2H, ³J=8.50 Hz, 7+8);8.21-8.23 (m; 1H, 12 or 15); 8.09-8.14 (m, 2H, NH+12 or 15); 8.00 (d,2H, ³J=8.50 Hz, 5+6); 7.60 (td, 1H, ³J=7.40 Hz, ⁴J=1.20 Hz, 13 or 14);7.53 (td, 1H, ³J=7.40 Hz, ⁴J=1.20 Hz, 13 or 14); 3.04 (t, 2H, ³J=6.90Hz, 3); 2.39 (qt, 2H, ³J₂₋₁=10.60 Hz, ³J₂₋₃=6.80 Hz, 2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=166.0 (10); 154.0 (16); 142.4 (9); 136.7(16); 135.3 (11); 128.5 (5+6); 128.1 (7+8); 127.5 (13 or 14); 126.6 (13or 14); 126.9 (q, ¹J_(C-F)=273.4 Hz, 1); 123.8 (15 or 12); 123.1 (15 or12); 36.5 (3); 33.7 (q, ²J_(C-F)=27.5 Hz, 2)

Compound 43: 4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

50 mg (1 eq.) 4-(2-methylthiazol-4-yl)benzoic acid, 37 mg (1.1 eq.)3,3,3-trifluoropropylamine hydrochloride (1.1 eq), 103 mg (1.2 eq.)HBTU, 52 mg (1.5 eq.) HOBt, 118 μL (3 eq.) DIEA and 2.5 mL DMF areintroduced in this particular order in a 10 mL flask. The solution isagitated during 2 h at AT. The DMF is evaporated under reduced pressure.The product is taken over in the ethyl acetate and then washedsuccessively by means of an aqueous solution saturated with K₂CO₃ (2×),an aqueous solution of HCl 1N (2×), of water (1×) and of brine (1×). Theorganic phase is dried on magnesium sulfate and then evaporated underreduced pressure to yield 67 mg (93%) of beige powder.

LC-MS: t_(R)=3.10 min (method c); m/z; [M+H]⁺=315

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.99 (d, 2H, ³J=8.50 Hz, 8+9); 7.87 (d,2H, ³J=8.50 Hz, 6+7); 7.76 (s, 1H, 12); 3.64 (t, 2H, ³J=7.00 Hz, 3);2.76 (s, 3H, 14); 2.54 (qt, 2H, ³J₂₋₁=10.60 Hz, ³J₂₋₃=6.80 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.4 (4); 167.1 (13); 153.6 (11); 137.4(10); 133.1 (5); 127.4 (6+7); 126.7 (q, ¹J_(C-F)=277.8 Hz, 1); 125.9(8+9); 114.7 (12); 33.1 (3); 32.7 (q, ²J_(C-F)=27.5 Hz, 2); 17.5 (14)

Compound 45: 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide

546.6 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 600 mg (1 eq.) 4-acetylbenzoic acid, 1.66 g (1.2 eq.) HBTU,98 mg (0.2 eq.) HOBt, and 2.53 mL (4 eq.) DIEA in 15 mL DMF. Thereaction medium is then agitated during 2 h at AT. The DMF is thenevaporated under reduced pressure. The orange oil thus obtained is takenover in the ethyl acetate and then washed by means of an aqueoussolution of HCl 1N (2×), an aqueous solution saturated with Na₂CO₃ (2×)and then in brine (1×). The organic phase is dried on magnesium sulfateand then evaporated under reduced pressure. The product thus obtained ispurified on a pre-packed silica column (Cyclohexane 85:15AcOEt→80:20→70:30) to yield 837 mg (88%) of white powder.

LC-MS: t_(R)=2.70 min (method c); m/z: [M+H]⁺=260

Compound 46: 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide

436.1 mg (1 eq.) trimethylphenylammonium tribromide are added to asolution of 300 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide(45) in a mixture of 15 mL DCE and 6 mL methanol. The solution isagitated at 50° C. 43.6 mg (0.1 eq) brominating reagent are added after1 h and 3 h of reaction. The DCE and the methanol are evaporated underreduced pressure. The product is taken over in the ethyl acetate andthen washed using water (2×) and in brine (1×). The organic phase isdried on magnesium sulfate and then evaporated under reduced pressure toyield 387 mg (99%) of beige powder.

LC-MS: t_(R)=2.93 min (method c); m/z: [M+H]⁺=340

Compound 47:4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46)are added to a solution of 43 mg (1 eq.) 5-methylhexanethioamide (37) in10 mL anhydrous THF. The reaction medium is heated under reflux during 3h. The THF is then evaporated under reduced pressure. The product istaken over in the ethyl acetate, washed in water (2×) and then in brine(1×). The organic phase is dried on magnesium sulfate and thenevaporated under reduced pressure. The beige solid thus obtained ispurified on a pre-packed silica column (Cyclohexane 9:1 AcOEt) to yield25 mg (22%) of powder beige.

LC-MS: t_(R)=3.77 min (method c); m/z: [M+H]⁺=385

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=7.99 (d, 2H, ³J=8.66 Hz, 8+9); 7.84 (d,2H, ³J=8.66 Hz, 6+7); 7.51 (s, 1H, 12); 6.83 (t, 1H, ³J=5.70 Hz, NH);3.73 (q, 2H, ³J=6.50 Hz, 3); 3.06 (t, 2H, ³J=7.77 Hz, 14); 2.53 (qt, 2H,³J₂₋₁=10.92 Hz ³J₂₋₃=6.78 Hz, 2); 1.87 (qn, 2H, ³J=7.85 Hz, 15); 1.66(n, 1H, ³J=6.65 Hz, 17); 1.36 (q, 2H, ³J=7.51 Hz, 16); 0.95; (d, 6H,³J=6.63 Hz, 18+19)

Compound 48: 3-methylbutanethioamide

1.01 g (0.5 eq.) Lawesson reagent and 16 mL anhydrous THF are added to505.8 mg (1 eq.) isovaleramide. The solution is agitated at AT during 4h and then THF is evaporated under reduced pressure. The product istaken over in the diisopropylic ether and then filtrated. The filtrateis then purified on a pre-packed silica column (DCM 100%) to yield 396mg (70%) of transparent oil that then crystallizes.

LC-MS: t_(R)=1.92 min (method c); m/z: [M+H]⁺=118

NMR ¹H (CDCl₃, 300 MHz): δ ppm=7.65 (br s, 1H, NH); 6.85 (br s, 1H, NH);2.52 (d, 2H, ³J=7.28 Hz, 2); 2.25 (n, 1H, ³J=6.95 Hz, 3); 1.00 (d, 6H,³J=6.59 Hz, 4+5)

Compound 49:4-(2-isobutylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46)are added to a solution of 34.7 mg (1 eq.) 3-methylbutanethioamide (48)in 6 mL anhydrous THF. The reaction medium is heated under reflux duringone night. 3.5 mg (0.1 eq) thioamide are added and the solution isagitated for a further 1 h under reflux. The THF is then evaporatedunder reduced pressure. The product is taken over in the ethyl acetate,washed in water (2×) and then in brine (1×). The organic phase is driedon magnesium sulfate and then evaporated under reduced pressure. Theresidue is purified using preparative HPLC to yield 78 mg (74%) of beigepowder.

LC-MS: t_(R)=3.17 min (method c); m/z: [M+H]⁺=357

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.01 (d, 2H, ³J=8.60 Hz, 8+9); 7.82 (d,2H, ³J=8.60 Hz, 6+7); 7.53 (s, 1H, 12); 6.47 (br s, 1H, NH); 3.74 (t,2H, ³J=6.50 Hz, 3); 2.95 (d, 2H, ³J=6.70 Hz, 14); 2.53 (qt, 2H,³J₂₋₁=10.80 Hz, ³J₂₋₃=6.50 Hz, 2); 2.19 (n, 1H, ³J=6.70 Hz, 15); 1.05(d, 6H, ³J=6.60 Hz, 16+17)

NMR ¹³C(CD₂Cl₂, 75 MHz): δ ppm=171.0 (13); 167.4 (4); 154.0 (11); 138.2(10); 133.6 (5); 127.8 (6+7); 127.1 (q, ¹J_(C-F)=277.8 Hz, 1); 126.7(8+9); 114.2 (12); 42.8 (14); 34.0 (q, ²J_(C-F)=27.5 Hz, 2); 33.8 (3);30.2 (15); 22.4 (16+17)

Compound 50:4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzamide

10 mg (1 eq,) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46)are added to a solution of 57.8 mg (1 eq.)2-(tert-butylsulfonyl)ethanethioamide in 6 mL anhydrous THF. Thereaction medium is agitated and heated under reflux during one night. Anadditional 11.7 mg (0.2 eq.) thioamide are added and the mixture isagitated for 2 h under reflux. The THF is then evaporated under reducedpressure. The product is taken over in the ethyl acetate, washed inwater (2×) and then in brine (1×). The organic phase is dried and thenevaporated under reduced pressure. The residue is purified on thepre-packed silica column (Cyclohexane 85:15 Isopropanol→Cyclohexane 1:1Isopropanol) to yield 98 mg (76%) of white powder.

LC-MS: t_(R)=5.23 min (method c); m/z: [M+H]⁺=435

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.76 (t, 1H, ³J=5.60 Hz, NH); 8.37 (s,1H, 12); 8.08 (d, 2H, ³J=8.40 Hz, 8+9); 7.93 (d, 2H, ³J=8.40 Hz, 6+7);5.09 (s, 2H, 14); 3.52 (q, 2H, ³J=6.50 Hz, 3); 2.57 (qt, 2H, ³J₂₋₁=10.94Hz, =6.62 Hz, 2); 1.39 (s, 9H, 16+17+18)

NMR ¹³C (DMSO-d₆, 75 MHz): δ ppm=166.3 (4); 157.2 (13); 153.7 (11);136.8 (5); 133.9 (10); 128.3 (6+7); 127.5 (q, ¹J_(C-F)=267 Hz, 1); 126.3(8+9); 119.3 (12); 60.6 (15); 50.8 (14); 33.3 (q, ³J_(C-F)=3.5 Hz, 3);32.9 (q, ²J_(C-F)=27.0 Hz, 2); 23.4 (16+17+18)

Compound 51:4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

107 mg (1.2 eq.) 2-cyanothioacetamide are added to a solution of 300 mg(1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 25mL THF. The medium is agitated during 24 h under reflux. The THF is thenevaporated under reduced pressure. The residue is taken over in theethyl acetate and then washed in brine (2×). The organic phase is driedon magnesium sulfate and then evaporated under reduced pressure to yield302 mg of orange solid. The raw product brut is thus used in thefollowing reaction.$

LC-MS: t_(R)=2.96 min (method c); m/z: [M−H]⁻=296

Compound 52:2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)ethylacetate

150 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46)are added to a solution of 44.4 mg (1 eq.) 2-cyanoethanethioamide in 10mL THF. The mixture is agitated during 15 h under reflux. The THF isevaporated under reduced pressure and the residue thus obtained is usedas is. Under argon, 515 μL (20 eq.) absolute ethanol and 545 μL (10 eq.)TMSCl are successively added at AT in a dry flask. The mixture is thenagitated at 40° C. during 2 h. 200 μL SOCl₂ are then added in 1 mLabsolute ethanol. The reaction medium is agitated at 40° C. during 2 hand then left to return to AT. 1 mL water is then added and the pH isneutralized by means of an aqueous solution saturated with NaHCO₃. Themixture is agitated for 15 min at AT and then extracted using ethylacetate. The organic phases are washed in brine (2×), dried on magnesiumsulfate and evaporated. The orange solid thus obtained is recrystallizedin 2 mL absolute ethanol to yield 58 mg (34%) of light brown crystals.

LC-MS: t_(R)=2.77 min (method c); m/z: [M+H]⁺=387

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.01 (d, 2H, ³J=8.50 Hz, 8+9); 7.83 (d,2H, ³J=8.50 Hz, 6+7); 7.65 (s, 1H, 12); 6.47 (br s, 1H, NH); 4.26 (q,³J=7.10 Hz, 16); 4.14 (s, 2H, 14); 3.73 (q, 2H, ³J=6.40 Hz, 3); 2.53(qt, 2H, ³J₂₋₁=10.9 Hz, ³J₂₋₃=6.60 Hz, 2); 1.32 (t, 3H, ³J=7.10 Hz, 17)

Compound 53:2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl(isopropylacetate

Under argon, 3.23 mL (48 eq.) isopropanol, 2.66 mL (24 eq.) TMSCl and300 mg (1 eq.)4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide (51)are successively added at AT in a dry flask. The solution is agitatedduring 10 min at AT and then 16 μL (1 eq.) water are added. The mixtureis then agitated at 40° C. during one night. The pH is neutralized bymeans of an aqueous solution saturated with NaHCO₃. The mixture isagitated 15 min at AT and then extracted using ethyl acetate. Theorganic phases are washed in brine (2×), dried on magnesium sulfate andevaporated. The residue thus obtained is then purified on a pre-packedsilica column (AcOEt 3:7 Cyclohexane) to yield 51 mg (15%) of whitesolid.

LC-MS: t_(R)=5.87 min (method d); m/z: [M+H]⁺=387

NMR ¹H (CDCl₃ 300 MHz): δ ppm=7.99 (d, 2H, ³J=8.60 Hz, 8+9); 7.83 (d,2H, ³J=8.60 Hz, 6+7); 7.58 (s, 1H, 12); 6.44 (m, 1H, NH); 5.14 (sp, 1H,³J=6.30 Hz, 16); 4.13 (s, 2H, 14); 3.77 (q, 2H, ³J=6.30 Hz, 3); 2.52(tq, 2H, ³J₂₋₁=10.8 Hz, ³J₂₋₃=6.30 Hz, 2); 1.32 (d, 6H, ³J=6.20 Hz,17+18)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=168.9 (4); 167.4 (13); 163.0 (15); 154.0(11); 137.9 (6); 133.9 (5); 127.9 (6+7); 127.3 (q, ¹J_(C-F)=277.0 Hz,1); 126.8 (8+9); 116.1 (12); 69.8 (16); 39.8 (14); 34.1 (q,²J_(C-F)=27.5 Hz, 2); 33.9 (3); 22.0 (17+18)

NMR ¹⁹F (CDCl₃, 282.4 MHz): δ ppm=−64.95 (t, ³J=10.8 Hz)

Compound 57:4-(2-(pyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

32.7 mg (1 eq.) thioisonicotinamide are added to a solution of 100 mg (1eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 6 mLTHF. The mixture is agitated during one night under reflux. The formedprecipitate is filtrated and then washed using di-ethylic ether. Theorange solid thus obtained is then taken over using ethyl acetate in aseparating funnel, washed with a solution saturated with K₂CO₃ and thenwith water (2×) and in brine (1×). The organic phase is dried onmagnesium sulfate and then evaporated under reduced pressure. Theresidue is purified on a pre-packed silica column (Cyclohexane 8:2Isopropanol) to yield 59 mg (66%) of yellow solid.

LC-MS: t_(R)=2.32 min (method c); m/z: [M+H]⁺=378

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.70 (m, 2H, 16+17); 8.20 (s, 1H, 12);8.18 (d, 2H, ³J=8.80 Hz, 8+9); 8.08 (m, 2H, 15+18); 7.94 (d, 2H, ³J=8.80Hz, 6+7); 3.67 (t, 2H, ³J=7.00 Hz, 3); 2.57 (qt, 2H, ³J₂₋₁=11.0 Hz,³J₂₋₃=7.00 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.5 (4); 164.7 (13); 155.9 (11); 149.9(16+17); 141.2 (14); 137.1 (5); 133.7 (10); 127.5 (6+7); 126.6 (q,¹J_(C-F)=278.1 Hz, 1); 126.2 (8+9); 120.6 (15+48); 117.2 (12); 33.1 (q,³J_(C-F)=3.3 Hz, 3); 32.7 (q, ²J_(C-F)=27.8 Hz)

Compound 58:4-(2-(2-ethylpyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

45 mg (1.1 eq.) ethionamide are added to a solution of 100 mg (1 eq.)4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 10 mL THF.The mixture is agitated under reflux during 24 h. The formed precipitateis filtrated and then washed using a solution of diethyl ether. Theyellow solid thus obtained is then taken over in the ethyl acetate in aseparating funnel, washed with a solution saturated with K₂CO₃ and thenusing water (2×) and in brine (1×). The organic phase is dried onmagnesium sulfate and then evaporated under reduced pressure to yield 75mg (63%) of yellow solid.

LCMS: t_(R)=3.12 min (method c); (m/z); [M+H]⁺=406

NMR ¹H (CDCl₃, 300 MHz): δ ppm=8.66 (d, 1H, ³J=5.30 Hz, 16); 8.09 (d,2H, ³J=8.50 Hz, 8+9); 7.86 (d, 2H, ³J=8.5 Hz, 6+7); 7.78 (s, 1H, 12);7.69 (m, 2H, 15+17); 6.45 (m, 1H, NH); 3.77 (q, 2H, ³J=6.30 Hz, 3); 2.94(q, 2H, ³J=7.60 Hz, 19); 2.52 (qt, 2H, ³J₂₋₁=10.80 Hz, ³J₂₋₃=6.40 Hz,2); 1.40 (t, 3H, ³J=7.60 Hz, 20)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=167.5 (4); 166.5 (13); 165.4 (18); 156.1(16); 150.6 (16); 140.9 (14); 137.6 (10); 134.4 (5); 128.1 (q,¹J_(C,F)=276.9 Hz, 1); 128.0 (6+7); 127.0 (8+9); 119.1 (17); 118.2 (15);116.4 (12); 34.26 (q, ²J_(C,F)=27.7 Hz, 2); 34.1 (3); 32.0 (19); 14.2(20)

Compound 54:4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-ethyl carboxylate

150 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide(46), 71 mg (1.2 eq.) ethyl thiooxamate and 15 mL THF are introduced ina 50 mL flask. The mixture is heated under reflux during 24 h. 11.5 mg(0.2 eq) thioamide are added and the solution is again agitated during24 h under reflux. 350 mg (3 eq.) PS-Tos-NHNH₂ resin are added and thereaction medium is agitated at AT during one night. The solution is thenfiltrated and the THF is then evaporated under reduced pressure. Theresidue is taken over in the ethyl acetate and then washed by means ofan aqueous solution saturated with K₂CO₃ (2×) and in brine (1×). Theorganic phase is dried on magnesium sulfate and then concentrated underreduced pressure. The residue thus obtained is purified on a pre-packedsilica column (Cyclohexane 8:2 AcOEt→Cyclohexane 7:3 AcOEt) to yield100.1 mg (61%) of powder beige.

LC-MS: t_(R)=3.22 min (method c); m/z: [M+H]⁺=373

NMR ¹H (CDCl₃ 300 MHz): δ ppm=8.05 (d, 2H, ³J=8.60 Hz); 7.81-7.85 (m,3H, 6+7+12); 6.44 (m, 1H, ³J=5.90 Hz, NH); 4.53 (q, 2H, ³J=7.10 Hz, 15);3.75 (q, ³J=6.30 Hz, 3); 2.50 (qt, 2H, ³J₂₋₁=10.80 Hz, ³J₂₋₃=6.60 Hz,2); 1.47 (t, 3H, ³J=7.10 Hz, 16)

Compounds 55:4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-isopropylcarboxylate and 56: 4-(thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide(46), 40 mg (1.1 eq.) ethyl thiooxamate and 10 mL THF are introduced ina 25 mL flask. The mixture is agitated during 24 h under reflux. The THFis evaporated under reduced pressure. The product is then solubilized in2.5 mL isopropanol.

In a flask cooled at 0° C., 20.4 mg (3 eq.) sodium are dissolved underargon in 2.5 mL isopropanol. The mixture is heated at 30° C. untilcomplete dissolution of the sodium. The solution in the isopropanolpreviously obtained is added drop by drop to this solution. The mixtureis then agitated during one night under reflux. 500 μL SOCl₂ are thenadded. The solution is agitated during one night at 50° C. The reactionmedium is evaporated under reduced pressure and both compounds 55 and 56formed in identical proportions are separated by preparative HPLC toyield 24 mg of 55 and 21.7 mg of 56.

Compound 55

LC-MS: t_(R)=4.90 min (method d); m/z: [M+H]⁺=387

NMR ¹H (CDCl₃, 300 MHz): δ ppm=8.07 (d, 2H, ³J=8.50 Hz); 7.84 (s, 1H,12); 7.85 (d, 2H, ³J=8.50 Hz, 6+7); 6.42 (m, 1H, NH); 5.37 (sp, 1H,³J=6.30 Hz, 15); 3.77 (q, 2H, ³J=6.30 Hz, 3); 2.52 (qt, 2H, ³J₂₋₁=10.70Hz, ³J₂₋₃=6.40 Hz, 2); 1.46 (d, 6H, ³J=6.30 Hz, 16+17)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=166.7 (4); 159.2 (13 or 14); 159.0 (13or 14); 156.0 (11); 136.6 (10); 134.1 (5); 127.5 (6+7); 126.7 (q,¹J_(C-F)=276.8 Hz, 1); 126.6 (8+9); 120.2 (12); 70.8 (15); 33.6 (q,²J_(C-F)=27.5 Hz, 2); 33.5 (q, ³J_(C-F)=3.6 Hz, 3); 21.5 (16+17)

Compound 56

LC-MS: t_(R)=5.82 min (method d); m/z: [M+H]⁺=301

NMR ¹H(CDCl₃, 300 MHz): δ ppm=8.92 (d, 1H, ⁴J=1.80 Hz, 13); 8.03 (d, 2H,³J=8.40 Hz, 8+9); 7.85 (d, 2H, ³J=8.40 Hz, 6+7); 7.64 (d, 1H, ⁴J=1.80Hz, 12); 3.77 (q, 2H, ³J=6.30 Hz, 3); 2.51 (qt, 2H, ³J₂₋₁=10.80 Hz,³J₂₋₃=6.40 Hz, 2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=166.8 (4); 155.0 (11); 153.3 (13); 137.3(10); 133.5 (5); 127.4 (6+7); 126.5 (8+9); 114.4 (12); 33.6 (q,²J_(C-F)=27.3 Hz, 2); 33.4 (3)

Compound 62:4-(5-fluoro-2-mthylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

101 mg (1 eq.) Selectfluor are added to a solution of 90 mg4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide (43) in 1.1mL anhydrous DMF. The solution is agitated during 15 h at 5° C. The LCMSanalysis of the reaction medium shows a very weak conversion of theinitial product. 0.5 eq Selectfluor are then added at 0° C. and thesolution is agitated during one night at 15° C. An additional 1 eq.Selectfluor is then added at 0° C. and the solution is then agitatedduring 24 h at AT. A conversion >70% is thus obtained. 1 mL of anammonia solution 2M in the ethanol as well as 0.5 mL of water are addedat 0° C. and the solution is agitated at AT during one night. Thesolvent is then evaporated under reduced pressure. The yellow oil thusobtained is taken over in the ethyl acetate and then washed using water(2×) and in brine (1×). The organic phase is dried on magnesium sulfateand then concentrated under reduced pressure. The yellow solid thusobtained is purified by preparative HPLC to yield 15 mg (16%) of whitepowder.

LC-MS: t_(R)=2.93 min (method c), 5.32 min (method d); m/z: [M+H]⁺=333

NMR ¹H (CD₂Cl₂ 300 MHz): δ ppm=7.97 (d, 2H, ³J=8.30 Hz, 8+9); 7.81 (d,2H, ³J=8.30 Hz, 6+7); 6.52 (br s, 1H, NH); 3.70 (q, 2H, ³J=6.50 Hz, 3);3.63 (d, 3H, ⁵J=2.30 Hz, 14); 2.50 (qt, ³J₂₋₁=10.90 Hz, ³J₂₋₃=6.70 Hz,2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=167.4 (4); 158.2 (d, ¹J_(C-F)=302.1 Hz,12); 154.5 (d, ³J_(C-F)=10.X Hz, 13); 135.7 (d, ³J_(C-F)=5.8 Hz, 10);133.6 (5); 133.5 (d, ²J_(C-F)=12.7 Hz, 11); 127.8 (6+7); 127.3 (d,⁴J_(C-F)=6.1 Hz, 8+9); 127.2 (q, ¹J_(C-F)=275.4 Hz 1); 34.2 (q,²J_(C-F)=27.0 Hz, 2), 34.0 (3); 20.7 (14)

Compound 64:4-(5-chloro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

50 mg (1 eq.) 4-(2-methylthiazol-4-yl)benzoic acid are added to asolution of 5 mL thionyle chloride. The mixture is agitated at 50° C.during 2 h. 2 mL thionyle chloride are then added and the solution isagitated for a further 2 h at 50° C. A third adjunction of 2 mL SOCl₂ isthen performed and the solution is agitated for a further 2 h at 50° C.The reaction medium is then evaporated under reduced pressure and theresidue thus obtained (compound 63) is taken over in thedichloromethane. 34 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochlorideand 158 μL (4 eq.) DIEA are added to the reaction medium and thesolution is agitated during one night at AT. The dichloromethane is thenevaporated under reduced pressure and the residue is then taken over inthe ethyl acetate. The organic phase is washed in brine (2×), dried onmagnesium sulfate and then evaporated under reduced pressure. The beigeoil thus obtained is then purified a first time on a pre-packed silicacolumn (Cyclohexane 85:15 iPrOH). The recovered white powder is notpure. The product is then purified on preparative HPLC to yield 23.5 mg(29%) of white powder.

LCMS: t_(R)=3.37 min (method c); m/z: [M+H]⁺=349, [M−H]⁻=347

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.08 (d, 2H, ³J=8.40 Hz, 8+9); 7.84 (d,2H, ³J=8.40 Hz, 6+7); 6.50 (m, 1H, NH); 3.74 (q, 2H, ³J=6.40 Hz, 3);2.70 (s, 3H, 14); 2.53 (qt, 2H, ³J₂₋₁=10.90 Hz, ³J₂₋₃=6.40 Hz, 2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=167.4 (4); 163.6 (13); 148.2 (11); 136.7(10); 134.1 (5); 128.8 (6+7); 127.4 (8+9); 127.3 (q, ¹J_(C,F)=277 Hz,1); 121.1 (12); 34.1 (q, ²J_(C,F)=27.6 Hz, 2); 34.0 (q, ³J_(C-F)=3.1 Hz,3); 20.1 (14)

Compound 65: 5-bromo-N-(3,3,3-trifluoropropyl)picolinamide

296 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 400 mg (1 eq.) 5-bromopicolinic acid, 1.40 mL (1.2 eq.) ofT3P solution at 50% in l′AcOEt and 1.03 mL (3 eq.) DIEA in 10 mLd′AcOEt. The mixture is agitated during 3 h at AT. Water and ethylacetate are then added. The organic phase is washed using water (2×) andthen in brine (1×), dried on magnesium sulfate and evaporated underreduced pressure to yield 433 mg (74%) of white solid.

LC-MS: t_(R)=2.58 min (method c); m/z: [M+H]⁺=297

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.73 (dd, 1H, ⁴J₇₋₈=2.25 Hz, ⁵J₈₋₆=0.52Hz, 8); 8.16 (dd, 1H, ³J₇₋₆=8.39 Hz, ⁴J₇₋₈ ⁼2.27 Hz, 7); 8.01 (dd, 1H,³J₆₋₇=8.33 Hz, ⁵J₆₋₈=0.59 Hz, 6); 3.67 (q, 2H, ³J=6.79 Hz, 3); 2.53 (qt,2H, ³J₂₋₁=10.99 Hz, ³J₂₋₃=7.11 Hz, 2)

Compound 66: 5-acetyl-N-(3,3,3-trifluoropropyl)picolinamide

400 mg (1 eq.) 5-bromo-N-(3,3,3-trifluoropropyl)picolinamide (65) areadded to a solution of 95 mg (0.1 eq.) PdCl₂(PPh₃)₂ in 3.5 mL toluene ina tube of Schlenk type under argon. The mixture is agitated during 5 minat AT and then 545 μL (1.2 eq.) tributyl(1-ethoxyvinyl)stannane areadded, still under argon. The reaction medium is then agitated duringone night at 90° C. The solution is cooled at AT and then 1 mL of anaqueous solution of hydrochloric acid 1N are added. The mixture is thenagitated during 1 h at AT. The reaction medium is neutralized by meansof an aqueous solution saturated with NaHCO₃ and then extracted usingethyl acetate. The organic phases are collected, washed in brine (2×),dried on magnesium sulfate and filtrated on celite. The yellow residuethus obtained is purified on a pre-packed silica column (Cyclohexane95:5 AcOEt→9:1→85:15→75:25→7:3) to yield 250 mg (71%) of white solid.

LC-MS: t_(R)=1.57 min (method c); m/z: [M+H]⁺=261

Compound 67:5-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)picolinamide

332 mg (1 eq.) trimethylphenylammonium tribromure are added to asolution of 230 mg (1 eq.)5-acetyl-N-(3,3,3-trifluoropropyl)picolinamide (66) in a mixture of DCE(12.5 mL)/MeOH (5 mL). The mixture is agitated during 24 h at 70° C. Themixture of solvent is then evaporated under reduced pressure. Theresidue is taken over in the ethyl acetate and washed in water and thenin brine. The organic phase is dried on magnesium sulfate and evaporatedunder reduced pressure to yield a yellow solid that is then solubilizedin 2 mL absolute EtOH. 101 mg (1.5 eq.) thioacetamide are then added andthe reaction medium is agitated during 4 h under reflux. The EtOH isevaporated under reduced pressure and the residue is taken over in theethyl acetate. The organic phase is washed using water (2×) and in brine(1×), dried on magnesium sulfate and then evaporated under reducedpressure. The residue is purified by preparative HPLC to yield 125 mg(45%) of white powder.

LC-MS: t_(R)=2.53 min (method c); m/z: [M+H]⁺=316

NMR ¹H (CD₃OD, 300 MHz): δ ppm=9.15 (dd, 1H, ⁴J₈₋₇=2.20 Hz, ⁵J₈₋₆=0.75Hz, 8); 8.40 (dd, 1H, ³J₇₋₆=8.18 Hz, ⁴J₇₋₈=2.23 Hz, 7); 8.12 (dd, 1H,³J₆₋₇=8.18 Hz, ⁵J₆₋₈=0.74 Hz, 6); 7.94 (s, 1H, 11); 3.69 (t, 2H, ³J=7.11Hz, 3); 2.78 (s, 3H, 13); 2.55 (qt, ³J₂₋₁=10.97 Hz, ³J₂₋₃=7.22 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=167.7 (12); 165.2 (4); 150.7 (10); 148.2(5); 146.2 (8); 134.3 (7); 132.7 (9); 126.5 (q, ¹J_(C-F)=275.9 Hz, 1);121.7 (6); 116.2 (11); 32.8 (q, ²J_(C-F)=27.8 Hz, 2); 32.6 (q,³J_(C-F)=3.7 HZ, 3); 17.5 (13)

Compound 68: 6-chloro-N-(3,3,3-trifluoropropyl)nicotinamide

700 mg (1 eq.) 6-chloro-nicotinic acid chloride are added to a solutionof 595 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride and 1.75 mL(4 eq.) N-methylmorpholine in 40 mL anhydrous DCM. The reaction mediumis agitated during 1 h at AT. An additional equivalent (700 mg) of acidchloride is added and the solution is agitated during one night at AT.The DCM is evaporated under reduced pressure. The solid thus obtained istaken over in a mixture of Cylohexane 1:1 Ethyl acetate and thenfiltrated on silica. The product is then purified on a pre-packed silicacolumn (Cyclohexane 7:3 AcOEt) to yield 918 mg (92%) of white powder.

LC-MS: t_(R)=2.32 min (method c); m/z: [M+H]⁺=253, [M−H]⁻=251

Compound 69: 6-iodo-N-(3,3,3-trifluoropropyl)nicotinamide

28 μL (0.2 eq.) acetic acid chloride are added under argon to a solutionof 500 mg (1 eq.) 6-chloro-N-(3,3,3-trifluoropropyl)nicotinamide (68),1.48 g (5 eq.) NaI in 15 mL acetonitrile in a carrousel tube. Thesolution is agitated at 105° C. during one night. The acetonitrile isevaporated under reduced pressure, the product is then taken over in theethyl acetate, filtrated, washed with an aqueous solution of Na₂SO₃ at10% and then with an aqueous solution of Na₂CO₃ at 5% and then in brine.The organic phase is then dried on magnesium sulfate and then evaporatedunder reduced pressure to yield 619 mg (91%) of white powder.

LC-MS: t_(R)=2.33 min (method c); m/z: [M+H]⁺=345, [M−H]⁻=343

Compound 70: 6-acetyl-N-(3,3,3-trifluoropropyl)nicotinamide

300 mg (1 eq.) 6-iodo-N-(3,3,3-trifluoropropyl)nicotinamide (69) areadded to a solution of 61 mg (0.1 eq.) PdCl₂(PPh₃)₂ in 2.6 mL toluene.The reaction medium is agitated for 5 min at AT and then 353 μL (1.2eq.) tributyl(1-ethoxyvinyl)stannane are added under argon. The reactionmedium is then agitated under argon during one night at 110° C. Thereaction medium is cooled at AT, and then 8 mL of an aqueous solution ofHCl 1N are added and the solution is agitated during 2 h at AT. Thereaction medium is neutralized by means of an aqueous solution saturatedwith NaHCO₃. The medium is extracted using ethyl acetate. The organicphases are collected, washed in brine (2×), dried on magnesium sulfateand filtrated on celite. The brown residue thus obtained is solubilizedin 5 mL acetonitrile and then filtrated. The filtrate is then purifiedby preparative HPLC to yield 89 mg (35%) of white powder.

LC-MS: t_(R)=4.10 min (method d); m/z: [M+H]⁺=261, [M−H]⁻=259

Compound 71:6-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)nicotinamide

129 mg (1 eq.) trimethylphenylammonium tribromide are added to asolution of 89 mg (1 eq.) 6-acetyl-N-(3,3,3-trifluoropropyl)nicotinamide(70) in 5.9 mL of a mixture DCE 5:2 MeOH. The reaction medium isagitated at 50° C. during 2 h. The LCMS analysis of the milieu shows aconversion rate close to zero, the reaction is then heated at 70° C.during 72 h. The LCMS analysis of the milieu shows an incompleteconversion of the reaction medium and the formation of two majorityproducts: mono-brominated ketone and mono-chlorinated ketone, as well asa little di-chlorinated ketone. The reaction is however stopped, and thesolvent mixture is evaporated under reduced pressure. The residue istaken over in 1 mL absolute ethanol. 26 mg (1 eq.) thioacetamide arethen added and the solution is agitated during 1 h under reflux. Anadditional 13 mg (0.5 eq.) are added and the reaction medium is agitatedduring 3 h under reflux and then cooled at AT. 6 mL diethyl ether areadded and the solution is cooled in a refrigerator during one night. Theformed precipitate is filtrated and then washed using diethyl ether. Theprecipitate is taken over in the ethyl acetate and then washed with anaqueous solution saturated with NaHCO₃ (2×) and then in brine (1×). Theorganic phase is then dried on magnesium sulfate and then evaporatedunder reduced pressure in order to yield 39 mg (34%) of white powder.

LC-MS: t_(R)=2.28 min (method c); m/z: [M+H]⁺=316, [M−H]⁻=314

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.97 (dd, 1H, ⁴J₆₋₇=2.29 Hz, ⁵J₆₋₈=0.84Hz, 6); 8.24 (dd, 1H, ³J₇₋₈=8.27 Hz, ⁴J₇₋₆=2.30 Hz, 7); 8.13 (dd, 1H,³J₈₋₇, =8.30 Hz, ⁵J₈₋₆=0.81 Hz, 8); 8.11 (s, 1H, 11); 3.65 (t, 2H,³J=7.00 Hz, 3); 2.76 (s, 3H, 13); 2.55 (qt, 2H, ³J₂₋₁=10.84 Hz,³J₂₋₃=7.13 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=167.3 (12); 166.4 (4); 154.4 (9); 153.4(10); 148.1 (6); 136.1 (7); 128.5 (5); 126.6 (q, ¹J_(C-F)=276.3 Hz, 1);120.3 (8); 118.8 (11); 33.1 (q, =9.74 Hz, 3); 32.6 (q, ²J_(C-F)=27.7 Hz,2); 17.6 (13)

Compound 72: 4-(2-methyloxazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide (45) areadded to a solution of 21 mg (1.2 eq.) acetamide in 300 μL toluene. Thereaction medium is agitated in a microwave reactor during 10 min at 110°C. (P_(max)=300W). 240 mg (3 eq.) Tos-NHNH₂ resin are added. Thesolution is agitated one night at AT and then filtrated. The solution istaken over in the ethyl acetate and then washed using water (2×) and inbrine (1×). The organic phase is dried on magnesium sulfate and thenevaporated under reduced pressure in order to yield 68 mg (77%) of beigepowder.

LC-MS: t_(R)=2.30 min (method c); m/z: [M+H]⁺=299, [M−H]⁻=297

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=7.97 (s, 12); 7.84-7.77 (m, 4H,6+7+8+9); 3.70 (q, 2H, ³J=6.50 Hz, 3); 2.60-2.44 (m, 3H, 14+2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=167.6 (4); 162.8 (13); 140.0 (11); 134.9(5 or 10); 134.8 (5 or 10); 133.6 (12); 127.8 (6+7 or 8+9); 127.1 (q,¹J_(C-F)=277.0 Hz, 1); 125.7 (6+7 or 8+9); 33.8 (q, ²J_(C-F)=27.1 Hz,2); 33.8 (q, ³J_(C-F)=3.7 Hz, 3); 14.0 (3)

Compound 73: 4-cyano-N-(3,3,3-trifluoropropyl)benzamide

305 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 300 mg (1 eq.) 4-cyanobenzoic acid, 1.46 mL (1.2 eq.) of T3Psolution at 50% in the ethyl acetate and 1.4 mL (4 eq.) DIEA in 3 mLethyl acetate. The reaction medium is agitated one night at AT. Thesolution is then washed using water (2×) and then in brine (1×). Theorganic phase is dried on magnesium sulfate, evaporated under reducedpressure to yield 424 mg (86%) of white solid.

LC-MS: t_(R)=2.31 min (method c); m/z: [M−H]⁻=241

NMR ¹H (CDCl₃, 300 MHz): δ ppm=7.86 (d, 2H, ³J=8.47 Hz, 6+7); 7.75 (d,2H, ³J=8.47 Hz, 8+9); 6.50 (br, s, 0.5H, NH); 3.74 (q, 2H, ³J=6.30 Hz;3); 2.49 (qt, 2H, ³J₂₋₁=10.69 Hz, ³J₂₋₃=6.38 Hz; 2)

Compound 74:4-(N′-hydroxycarbamimidoyl)-N-(3,3,3-trifluoropropyl)benzamide

300 mg (1 eq.) 4-cyano-N-(3,3,3-trifluoro-propyl)-benzamide (73) areadded to a solution of 129 mg (1.5 eq.) hydroxylamine hydrochloride and343 μL (1.6 eq.) DIEA in 2.5 mL ethanol. The solution is agitated underreflux during 2 h. The solvent is then evaporated under reducedpressure. The residue is taken over in the ethyl acetate and then washedusing water (2×) and in brine (1×). The organic phase is dried onmagnesium sulfate and evaporated under reduced pressure to yield 330 mg(97%) of white powder.

LC-MS: t_(R)=3.74 min (method d); m/z: [M−H]⁻=274

NMR ¹H DMSO-d₆ 300 MHz): δ ppm=9.79 (s, 1H, OH); 8.70 (t, 1H, ³J=5.52Hz, NH-amide); 7.83 (d, 2H, ³J=8.55 Hz, 6+7 or 8+9); 7.77 (d, 2H,³J=8.48 Hz, 7+6 or 8+9); 5.89 (s, 2H, NH₂); 3.50 (q, 2H, ³J=6.49 Hz, 3);2.55 (qt, 2H, ³J₂₋₁=11.42 Hz, ³J₂₋₃=6.94 Hz, 2).

Compound 75:4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3,3,3-trifluoropropyl)benzamide

330 mg (1 eq.)4-(N′-hydroxycarbamimidoyl)-N-(3,3,3-trifluoropropyl)benzamide (74) areadded to a solution of 78 μL (1.1 eq.) acetic acid, 1.84 mL (2.5 eq.) ofT3P solution at 50% in the ethyl acetate and 643 μL (3 eq.) DIEA in 9 mLethyl acetate. The solution is agitated during one night under reflux.The conversion is incomplete. The reaction medium is then evaporatedunder reduced pressure. 1 mL ethyl acetate, 368 μL (0.5 eq) T3P and 107μL (0.5 eq.) DIEA are added. The solution is agitated during 48 h underreflux. 2 mL of water are then added and the reaction is agitated during15 min at AT The organic phase is then washed using water (2×) and thenin brine (1×), dried on magnesium sulfate and evaporated under reducedpressure. The residue thus obtained is purified on a pre-packed silicacolumn (Cyclohexane 9:1 Isopropanol) to yield 215 mg (66%) of whitesolid.

LC-MS: t_(R)=2.37 min (method c); m/z: [M+H]⁺=300, [M−H]⁻=298

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.86 (t, 1H, ³J=5.54 Hz, NH); 8.09 (d,2H, ³J=8.46 Hz, 8+9); 7.99 (d, 2H, ³J=8.55 Hz, 6+7); 3.52 (q, 2H,³J=6.42 Hz, 3); 2.68-2.50 (m, 5H, 13+2)

NMR ¹³C (DMSO-d₆ 75 MHz): δ ppm=177.8 (12); 167.1 (11); 165.6 (4); 136.6(5); 128.8 (10); 128.1 (6+7); 127.0 (8+9); 126.9 (q, =277.12 Hz, 1);32.9 (3); 32.4 (q, 2J_(C-F)=27.1 Hz, 2)

Compound 76: 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate

1.66 g (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 2 g (1 eq.) mono-methylterephtalate, 5.04 g (1.2 eq.) HBTU,0.3 g (0.2 eq.) HOBt and 7.7 mL (4 eq.) DIEA in 45.5 mL DMF on amolecular sieve. The reaction medium is agitated at AT during 1 h. TheDMF is then evaporated under reduced pressure. The residue is taken overin the ethyl acetate and then washed with a solution saturated withNaHCO₃ (2×), a solution of hydrochloric acid 1N (2×) using water (1×)and in brine (1×). The organic phase is then dried on magnesium sulfateand then evaporated under reduced pressure. The residue thus obtained ispurified on a pre-packed silica column (Cyclohexane 9:1AcOEt→Cyclohexane 85:15 AcOEt) to yield 1.25 g (41%) of white powder.The impure fractions are again purified on a pre-packed silica column(Cyclohexane 9:1 AcOEt) to yield 1.27 g (41%) of white powder. Thisresults in a yield of 82%.

LCMS: t_(R)=2.44 min (method c); m/z: [M−H]⁻=274

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm: 8.10 (d, 2H, ³J=8.63 Hz, 8+9 or 6+7);7.83 (d, 2H, ³J=8.55 Hz, 7+6 or 8+9); 6.60 (br s, 1H, NH); 3.95 (s, 3H,12); 3.74 (q, 2H, ³J=6.45 Hz, 3); 2.53 (qt, 2H, ³J₂₋₁=10.93 Hz,³J₂₋₃=6.63 Hz, 2)

Compound 77: 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid

300 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate (76)are added to a solution of 244.6 mg (4 eq.) potassium hydroxide in 2.66mL MeOH. The mixture is agitated under reflux during 2 h. The reactionmedium is then evaporated under reduced pressure. The white solid thusobtained is taken over in a mixture water: AcOEt. The aqueous phase iswashed using ethyl acetate and then acidified by means of an aqueoussolution of hydrochloric acid 1N up to pH=2. The formed whiteprecipitate is then solubilized in the ethyl acetate. The organic phaseis washed using water (2×) and then in brine (1×), dried on magnesiumsulfate and then concentrated under reduced pressure to yield 254 mg(89%) of white powder.

LC-MS: t_(R)=4.28 min (method d); m/z: [M−H]⁻=260

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=13.21 (br s, 1H, COOH); 8.84 (t, 1H,³J=5.56 Hz, NH); 8.02 (d, 2H, ³J=8.25 Hz, 6+7 or 8+9); 7.91 (d, 2H,³J=8.25 Hz, 6+7 or 8+9); 3.50 (q, 2H, ³J=6.30 Hz, 3); 2.55 (qt, 2H,³J₂₋₁=11.44 Hz, ³J₂₋₃=6.96 Hz, 2)

Compound 78:4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid (77) areadded to a solution of 28.4 mg (1 eq.) acetamidoxime, 570 μL (2.5 eq.)of T3P solution at 50% in the ethyl acetate, 199 μL (3 eq.) DIEA in 191μL ethyl acetate. The mixture is agitated under reflux during 12 h. TheCCM analysis of the medium shows an incomplete conversion. 228 μL (1eq.) of T3P solution and 66 μL (1 eq.) DIEA are then added. The reactionis agitated for a further 24 h under reflux. 200 μL of water are addedto the reaction medium at AT and the solution is agitated during 10 minat AT. The product is purified by preparative HPLC to yield 88 mg (77%)of white powder.

LC-MS: t_(R)=3.00 min (method c); m/z: [M−H]⁻=298

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.21 (d, 2H, ³J=8.42 Hz, 8+9); 7.91 (d,2H, ³J=8.42 Hz, 6+7); 6.54 (br s, H, NH); 3.75 (q, 2H, ³J=6.41 Hz, 3);2.61-2.46 (m, 5H, 13+2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=174.8 (4); 168.5 (12); 166.6 (4); 138.1(5); 128.6 (8+9); 128.0 (6+7); 127.4 (10); 127.0 (q, ¹J_(C-F)=276.8 Hz,1); 34.0 (3); 33.9 (q, ²J_(C-F)=27.6 Hz, 2); 11.9 (13)

Compound 80:4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzamide

100 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid (77) areadded to a solution of 31.2 mg (1.1 eq.) acetylhydrazine, 570 μL (2.5eq.) of T3P solution at 50% in the ethyl acetate and 199 μL (3 eq.) DIEAin 196 μL ethyl acetate. The solution is agitated during 24 h underreflux. The LCMS analysis of the reaction medium shows the formation of50% of the desired product and of 50% of the non-cyclized intermediateproduct. 66 μL (1 eq.) DIEA and 228 μL of T3P solution at 50% in theethyl acetate are then added and the solution is agitated during 48 hunder reflux. The solution is left to return at AT and then 1 mL ofwater is added and the mixture is agitated during 15 min at AT. Theorganic phase is then washed using water (2×) and in brine (1×), driedon magnesium sulfate and evaporated under reduced pressure to yield 102mg (90%) of white powder.

LC-MS: t_(R)=4.68 min (method d); m/z: [M−H]⁻=298

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.07 (d, 2H, ³J=8.44 Hz, 8+9); 7.88 (d,2H, ³J=8.44 Hz, 6+7); 6.73 (br s, 1H, NH); 3.72 (q, 2H, ³J=6.46 Hz, 3);2.60 (s, 3H, 13); 2.50 (qt, 2H, ³J₂₋₁=10.85 Hz, ³J₂₋₃=6.64 Hz, 2)

NMR ¹³C (CD₂Cl₂, 75 MHz): δ ppm=166.8 (4); 164.7 (12); 164.5 (11); 137.2(5); 128.1 (6+7); 127.2 (10); 127.2 (8+9); 127.0 (q, ¹J_(C-F)=275.9 Hz,1); 34.1 (q, ³J_(C-F)=2.8 Hz, 3); 33.9 (q, ²J_(C-F)=27.7 Hz, 2); 11.3(13)

Compound 81: 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzonitrile

482 mg (1.5 eq.) Lawesson reagent are added at AT to a solution of 100mg (1 eq.) 4-cyanobenzoic acid, 51 mg (1 eq.) acetylhydrazine, 606 μL(1.5 eq.) of T3P solution at 50% in the ethyl acetate and 295 μL (2.5eq.) DIEA in 1.5 mL ethyl acetate. The solution is then heated duringone night under reflux. The reaction medium is cooled at AT and then 5mL of water are added. The solution is agitated during 15 min at AT. Theorganic phase is washed with an aqueous solution saturated with NaHCO₃(2×) and then in brine (1×), dried on magnesium sulfate and evaporatedunder reduced pressure. The yellow oil thus obtained is used as is inthe following reaction.

LC-MS: t_(R)=2.10 min (method c); m/z: [M+H]⁺=202

Compound 82: 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzoic acid

137 mg (1 eq.) 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzonitrile (81) areadded to 5 mL of an aqueous soda solution at 10%. The mixture isagitated during 1 h under reflux and then cooled at AT and finallywashed using ethyl acetate. The aqueous phase is then acidified by meansof a solution of HCl 1N up to pH=2 and then extracted using ethylacetate. The organic phases are collected, dried on magnesium sulfateand then evaporated under, reduced pressure. The product is used as isin the following step.

LC-MS: t_(R)=1.65 min (method c); m/z: [M−H]⁻=219

Compound 83:4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzamide

101 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 150 mg (1 eq.) 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzoicacid (82), 485 μL (1.2 eq.) of T3P solution at 50% in the ethyl acetateand 353 μL (3 eq.) DIEA in 3 mL ethyl acetate. The solution is agitatedduring one night at AT. 81 μL (0.2 eq.) of T3P solution are added andthe mixture is agitated during 4 h at AT. 2 mL of water are added andthe reaction medium is agitated during 15 min at AT. The organic phaseis washed using water (2×) and then in brine (1×), dried on magnesiumsulfate and then evaporated under reduced pressure. The residue thusobtained is purified on a pre-packed silica column (DCM→DCM 99:1MeOH→DCM 98:2 MeOH) to yield 22 mg (10%) of white powder.

LC-MS: t_(R)=2.17 min (method c); m/z: [M+H]⁺=316, [M−H]⁻=314

NMR ¹H (CD₂Cl₂, 300 MHz): δ ppm=8.04 (d, 2H, ³J=8.71 Hz, 8+9); 7.95 (d,2H, ³J=8.71 Hz, 6+7); 3.65 (t, 2H, ³J=6.99 Hz, 3); 2.83 (s, 3H, 13);2.55 (qt, ³J₂₋₁=10.88 Hz, ³J₂₋₃=7.10 Hz, 2)

NMR ¹³C (CD₂Cl₂, 300 MHz): δ ppm=169.7 (11); 169.1 (4); 168.4 (12);137.7 (5 or 10); 134.0 (5 or 10); 129.3 (6+7); 128.9 (8+9); 128.0 (q,¹J_(C-F)=276.3 Hz, 1); 34.5 (3); 34.0 (q, ²J_(C-F)=27.8 Hz, 2)

Compound 84: N1-(3,3,3-trifluoropropyl)terephthalamide

2 mL ammonia solution 7N in the methanol are added to a solution of 200mg 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate (76) in 2 mLmethanol. The solution is agitated during 36 h under reflux. The LCMSand CCM analyses of the reaction medium show nearly no conversion of thestarting ester. 500 μL of water and 163 mg (4 eq.) KOH are then addedand the reaction medium is agitated during one night under reflux. Thesolution is acidified up, to pH=4 by means of a solution of hydrochloricacid 1N. The formed white precipitate is filtrated and dried one nightin a desiccator (148 mg).

The product is then solubilized in 10 mL of a mixture DCE:SOCl₂ (1:1).The, solution is agitated during 4 h at 50° C. The solution isconcentrated under reduced pressure and then taken over at 0° C. in 15mL of a mixture CH₃CN:NH₄OH 28% (2:1). The solution is, agitated at ATfor one night. The reaction medium is extracted using ethyl acetate. Theorganic phases are regrouped and then washed using water (2×) and inbrine (1×), dried on magnesium sulfate and evaporated under reducedpressure to yield 115 mg (61%) of white solid.

LC-MS: t_(R)=1.77 min (method c); m/z: [M−H]⁻=259

Compound 85:4-(2-oxo-1,3,4-oxathiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide

75 μL (2 eq.) (chlorothio)formyle chloride are added to a solution of115 mg (1 eq.) N1-(3,3,3-trifluoropropyl)terephthalamide (84) in 1.1 mLtoluene. The reaction medium is agitated during 24 h at 90° C. 38 μL (1eq.) (chlorothio)formyle chloride are then added and the reaction isagitated at 90° C. during a further 24 h. The toluene is evaporatedunder reduced pressure. The residue is taken over in somedichloromethane and then filtrated to yield 95 mg (68%) of white solid.

LC-MS: t_(R)=2.57 min (method c); m/z: [M−H]⁻=317

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.90 (t, 1H, ³J=5.67 Hz, NH); 8.05-8.00(m, 4H, 6+7+8+9); 3.52 (q, 2H, ³J=6.44 Hz, 3); 2.57 (qt, 2H, ³J₂₋₁=11.34Hz, ³J₂₋₃=6.70 Hz, 2)

Compound 89:3-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1,2,4-thiadiazole-5-ethylcarboxylate

383 mL (10 eq.) ethyl cyanoformiate are added to a solution of 100 mg (1eq.) 4-(2-oxo-1,3,4-oxathiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide(85) in 400 μL 1,2-dichloro-benzene. The mixture is agitated during 30min at 160° C. in a microwave reactor. The solution is cooled at AT andthen 6 mL acetonitrile are then added. The formed precipitate isfiltrated to yield 302 mg (85%) of white powder.

LC-MS: t_(R)=2.77 min (method c); m/z: [M+H]⁺=374

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.44 (d, 2H, ³J=8.56 Hz, 8+9); 7.97 (d,2H, ³J=8.56 Hz, 6+7); 4.54 (q, 2H, ³J=7.16 Hz, 14); 3.66 (t, 2H, ³J=7.04Hz, 3); 2.55 (qt, 2H, ³J₂₋₁=10.83 Hz, ³J₂₋₃=7.04 Hz, 2); 1.47 (t, 3H,³J=7.13 Hz, 15)

Compound 90:4-(5-(hydroxymethyl)-1,2,4-thiadiazol-3-yl)-N-(3,3,3-trifluoropropyl)-benzamide

550 μL of a solution 2M of LiBH₄ in the THF are added at 0° C. and underargon to a solution of 140 mg3-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1,2,4-thiadiazole-5-ethylcarboxylate (89) in 3.5 mL anhydrous THF. The solution is agitatedduring 30 min at 0° C. 0.5 mL of an aqueous solution saturated withNH₄Cl are then added to neutralize the excess of hydride. The medium isconcentrated under reduced pressure. The residue thus obtained is thenpurified on a pre-packed silica column (Toluene 97:3 MeOH Toluene 95:5MeOH) to yield 108 mg (44%) of white powder.

LC-MS: t_(R)=2.18 min (method c); m/z: [M+H]⁺=332, [M−H]⁻=330

Compound 92: 4-azido-N-(3,3,3-trifluoropropyl)benzamide

1.05 g (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to asolution of 1.14 g (1 eq.) 4-azidobenzoic acid, 536 mg (0.5 eq) HOBt3.19 g (1.2 eq) HBTU and 4.85 mL (4 eq.) DIEA in 5 mL DMF. The solutionis agitated one night at AT and then evaporated under reduced pressure.The residue is dissolved in the ethyl acetate and washed with an aqueoussolution saturated with NaHCO₃ (2×), an aqueous solution of HCl 1N (1×)and in brine (1×). The organic phase is dried on magnesium sulfate andthen evaporated under reduced pressure to yield 1.77 g (98%) of a lightbrown solid.

LC-MS: t_(R)=2.65 min (method c); m/z: [M−H]⁻=257

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.86 (d, 2H, ³J=8.91 Hz, 6+7 or 8+9);7.15 (d, 2H, ³J=8.92 Hz, 6+7 or 8+9); 3.61 (t, 2H, ³J=6.97 Hz, 3); 2.51(qt, =10.99 Hz, ³J₂₋₃=7.05 Hz, 2)

Procedure (ii): General Procedure for Forming Triazole by “ClickChemistry”

1 eq. alkyne is added to a solution of 115 mg (1 eq.)4-azido-N-(3,3,3-trifluoropropyl)benzamide (92), 8 mg (0.1 eq.) CuSO₄,99.1 mg (1 eq.) sodium ascorbate in 6 mL of a mixture t-BuOH/H₂O (1/1).The solution is agitated one night at AT.

Compound 93:4-(4-isopentyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)benzamide

Procedure (ii) with 65.7 μL 5-methylhexyne. The medium is filtratedafter reaction. The product still present in the aqueous phase isextracted using ethyl acetate. The product is then dried in a desiccatorto yield 93 mg (53%) of beige solid.

LC-MS: t_(R)=2.93 min (method c); m/z: [M+H]⁺=355

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.84 (br s, 1H, NH); 8.69 (s, 1H, 11);8.03 (br m, 4H, 6+7+8+9); 3.53 (q, 2H, ³J=6.34 Hz, 3); 2.73 (t, 2H,³J=7.42 Hz, 13); 2.58 (qt, ³J₂₋₁=11.40 Hz, ³J₂₋₃=7.11 Hz, 2); 1.67-1.54(m, 3H, 14+15); 0.94 (d, 6H, ³J=6.13 Hz, 16+17)

Compound 94:4-(4-isobutyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)benzamide

Procedure (ii) with 58.9 μL 4-methylpentyne. After one night, theconversion is not total. 1 eq. alkyne, 0.5 eq. sodium ascorbate and 0.05eq. CuSO₄ are added to the reaction medium. The solution is agitatedduring 4 h at AT. The product is extracted using ethyl acetate. Theorganic phases are collected, dried on magnesium sulfate and thenevaporated under reduced pressure to yield 128 mg (75%) of a light brownpowder.

LC-MS: t_(R)=2.77 min (method c); m/z: [M+H]⁺=341

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.42 (s, 1H, 11); 8.05-7.97 (m, 4H,6+7+8+9); 3.65 (t, 2H, ³J=6.98 Hz, 3); 2.67 (d, 2H, ³J=6.85 Hz, 13);2.55 (qt, ³J₂₋₁=10.93 Hz, ³J₂₋₃=6.93 Hz, 2); 2.03 (n, 1H, ³J=6.75 Hz,14); 0.99 (d, 6H, ³J=6.63 Hz, 15+16)

Compound 95:4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

Procedure (ii) with 42.4 μL ethynylcyclopropane. Part of the product isrecovered by filtration of the formed precipitate. The remaining productin the filtrate is extracted using ethyl acetate. The organic phases arecollected, dried on magnesium sulfate and then evaporated under reducedpressure to yield 73 mg (45%) of a white powder.

LC-MS: t_(R)=2.52 min (method c); m/z: [M+H]⁺=325

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=8.84 (br s, 1H, NH); 8.64 (s, 1H, 11);8.05-7.97 (m, 4H, 6+7+8+9); 3.53 (q, 2H, ³J=6.44 Hz, 3); 2.58 (qt, 2H,³J₂₋₁=11.51 Hz, ³J₂₋₃=6.95 Hz, 2); 2.09-2.00 (m, 1H, 13);1.02-0.96+0.84-0.79 (m, 4H, 14+15)

Compound 96:4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

Procedure (ii) with 29.2 μL propargyl alcohol. The product is extractedusing ethyl acetate. The organic phases are regrouped, dried onmagnesium sulfate and then evaporated under reduced pressure to yield 52mg (33%) of a beige powder.

LC-MS: t_(R)=2.03 min (method c); m/z: [M+H]⁺=315

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.57 (s, 1H, 11); 8.07-7.99 (m, 4H,6+7+8+9); 4.79 (s, 2H, 13); 3.67 (t, 2H, ³J=6.97 Hz, 3); 2.57 (qt, 2H,³J₂₋₁=10.91 Hz, ³J₂₋₃=6.98 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.9 (4); 150.3 (12); 140.6 (5 or 10);135.5 (5 or 10); 130.1 (6+7); 128.0 (q, ¹J_(C-F)=276.1 Hz, 1); 122.3(11); 121.2 (8+9); 56.4 (13); 34.6 (3); 34.0 (q, ²J_(C-F)=27.7 Hz, 2)

Compound 97:4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

Procedure (ii) with 37.9 μL 3-butyn-1-ol. No precipitate is observed.The product is extracted using ethyl acetate. The organic phases arecollected, dried on magnesium sulfate and then evaporated under reducedpressure to yield 135 mg (82%) of beige solid.

LC-MS: t_(R)=2.07 min (method c); m/z: [M+H]⁺=329

NMR ¹H (CD₃OD, 300 MHz): δ ppm=8.44 (s, 1H, 11); 8.04-7.96 (m, 4H,6+7+8+9); 3.89 (t, 2H, ³J=6.62 Hz, 14); 3.65 (t, 2H, ³J=6.98 Hz, 3);3.00 (t, 2H, ³J=6.51 Hz, 13); 2.44 (qt, 2H, ³J₂₋₁=10.85 Hz, ³J₂₋₃=7.09Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=168.9 (4); 147.3 (12); 140.7 (5 or 10);135.4 (5 or 10); 130.1 (6+7); 128.0 (q, ¹J_(C-F)=275.8 Hz, 1); 122.2(11); 121.1 (8+9); 61.9 (14); 34.6 (3); 34.0 (q, ²J_(C-F)=28.1 Hz, 2);29.9 (13)

Compound 98:4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoro-propyl)benzamide

Procedure (ii) with 48.9 μL 2-methyl-3-butyn-2ol. Part of the product isrecovered by filtration of the formed precipitate. The remaining productin the filtrate is extracted using ethyl acetate. The organic phases arecollected, dried on magnesium sulfate and then evaporated under reducedpressure. The product is dried in a desiccator to yield 80 mg (53%) ofwhite powder.

LC-MS: t_(R)=2.18 min (method c); m/z: [M−H]⁻=341

NMR ¹H DMSO-d₆ 300 MHz): δ ppm=8.84 (t, 1H, ³J=5.18 Hz, NH); 8.71 (s,1H, 11); 8.08-8.01 (m, 4H, 6+7+8+9); 5.29 (s, 1H, OH); 3.53 (q, 2H,³J=6.40 Hz, 3); 2.58 (qt, 2H, ³J₂₋₁=11.53 Hz, ³J₂₋₃=6.72 Hz, 2)

Compound 99:1-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1H-1,2,3-triazole-4-methylcarboxylate

Procedure (ii) with 41.4 μL methyl propiolate. After one night, theconversion is not total. 0.5 eq. alkyne, 0.5 eq. sodium ascorbate and0.05 eq. CuSO₄ are added to the reaction medium. The solution isagitated during 4 h at AT. The product is extracted using ethyl acetate.The organic phases are collected, dried on magnesium sulfate and thenevaporated under reduced pressure to yield 156 mg (91%) of a beigepowder.

LC-MS: t_(R)=2.37 min (method c); m/z: [M+H]⁺=343

NMR ¹H (DMSO-d₆, 300 MHz): δ ppm=9.62 (s, 1H, 11); 8.89 (t, 1H, ³J=5.56Hz, NH); 8.14 (d, 2H, ³J=8.88 Hz, 8+9); 8.06 (d, 2H, ³J=8.88 Hz, 6+7);3.91 (s, 3H, 14); 3.54 (q, ³J=6.46 Hz, 3); 2.59 (qt, 2H, ³J₂₋₁=11.44 Hz,³J₂₋₃=7.06 Hz, 2)

NMR ¹³C (DMSO-d₆, 75 MHz): δ ppm=165.1 (13); 160.5 (4); 139.7 (12);138.0 (5 or 10); 134.5 (5 or 10); 128.9 (6+7); 127.5 (11); 126.9 (q,¹J_(C-F)=277.1 Hz, 1); 120.2 (8+9); 52.1 (14); 32.9 (3); 32.4 (q,²J_(C-F)=26.6 Hz, 2)

Compound 100: 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzimidatehydrochloride

15 mL of a solution of hydrochloric acid 4N in dioxane are added underargon at 0° C. to a solution of 300 mg4-cyano-N-(3,3,3-trifluoropropyl)benzamide (73) in 1 mL MeOH. Themixture is agitated during one night at AT. 20 mL diethyl ether areadded and the solution is cooled in a refrigerator during one hour. Theprecipitate is then filtrated, washed using diethyl ether and dried in adesiccator to yield 359 mg (93%) of white powder.

LC-MS: t_(R)=1.85 min (method c); m/z: [M+H]⁺=275, [M−H]⁻=273

Compound 101:4-(5-methyl-4H-1,2,4-triazol-3-yl)-N-(3,3,3-trifluoropropyl)benzamide

169 μL (1.5 eq.) DIEA are added to a solution of 200 mg4-(3,3,3-trifluoropropylcarbamoyl) methyl benzimidate hydrochloride(100) in 5 mL absolute ethanol. The reaction medium is agitated during15 min at AT. The acetylhydrazine is then added and the solution isagitated during 60 h under reflux. The ethanol is evaporated underreduced pressure. The solid rose thus obtained is purified bypreparative HPLC and then lyophilized to yield 123 mg (64%) of whitepowder.

LC-MS: t_(R)=1.92 min (method c); m/z: [M+H]⁺=299, [M−H]⁻=297

NMR ¹H (CD₃OD, 300 MHz 8.08 (d, 2H, ³J=8.59 Hz, 8+9); 7.90 (d, 2H,³J=8.68 Hz, 6+7); 3.64 (t, 2H, ³J=7.02 Hz, 3); 2.62-2.46 (m, 5H, 13+2)

Compound 102: (4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)methanaminium di-bromhydrate

73 mg (1.1 eq.) N-benzyloxycarbonylglycine thioamide are added to asolution of 100 mg (1 eq.)4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 5 mLanhydrous THF. The solution is agitated during 3 h at 70° C. The THF isthen evaporated under reduced pressure and the solid thus obtained isused as is 1 mL of a HBr solution at 25% in the acetic acid is added andthe reaction medium is agitated during 1 h at AT 8 mL diethyl ether arethen added at AT to form a precipitate that is cooled in an ice-waterbath. The precipitate is then filtrated, washed using cold diethyl etherand then dried in a desiccator to yield 157 mg of pale brown solid. Theproduct is separated in two for the synthesis of the compounds 103 and104.

LC-MS: t_(R)=1.85 min (method c); m/z: [M+H]⁺=330

Compound 103:4-(2-(propylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

20 μL (1.2 eq.) propane sulfonic acid chloride are added to a solutionof 75 mg (1 eq.) of compound 102 and 82 μL N-methylmorpholine in 1.5 mLanhydrous DCM. The reaction medium is agitated during 2 h at AT. The DCMis evaporated under reduced pressure and then the residue is taken overin the ethyl acetate and then washed using water (2×) and in brine (1×).The organic phase is dried on magnesium sulfate and then evaporatedunder reduced pressure to yield 54 mg (76%) of beige powder.

LC-MS: t_(R)=2.60 min (method c); m/z: [M−H]⁻=434

NMR ¹H (CD₃OD, 300 MHz): δ ppm: 8.05 (d, 2H, ³J=8.43 Hz, 8+9); 7.96 (s,1H, 12); 7.89 (d, 2H, ³J=8.49 Hz, 6+7); 4.63 (s, 2H, 14); 3.66, (t, 2H,³J=6.99 Hz, 3); 3.15-3.09 (m, 2H, 15); 2.56 (qt, 2H, ³J₂₋₁=10.89 Hz,³J₂₋₃=7.11 Hz, 2); 1.84 (sx, 2H, ³J=7.60 Hz, 16); 1.04 (t, 3H, ³J=7.46Hz, 17).

Compound 104:4-(2-(phenylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoro-propyl)benzamide

23 μL (1.2 eq.) benzene sulfonic acid chloride are added to a solutionof 75 mg (1 eq.) of compound 102 and 82 μL N-methylmorpholine in 1.5 mLanhydrous DCM. The reaction medium is agitated during 2 h at AT. The DCMis evaporated under reduced pressure and then the residue is taken overin the ethyl acetate and then washed using water (2×) and in brine (1×).The organic phase is dried on magnesium sulfate and then evaporatedunder reduced pressure to yield 51 mg (67%) of beige powder.

LC-MS: t_(R)=2.73 min (method c); m/z: [M−H]⁻=468

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.96 (d, ³J=8.50 Hz, 8+9); 7.87 (m, 5H,6+7+12+16+20); 5.57 (m, 3H, 17+18+19); 4.47 (s, 2H, 14); 3.65 (t, 2H,³J=7.00 Hz, 3); 2.55 (qt, 2H, ³J₂₋₁=11.0 Hz, ³J₂₋₃=7.10 Hz, 2)

Compound 105: N-(prop-2-ynyl)benzene sulfonamide

200 μL (1 eq.) benzene sulfonic acid chloride, 129 μL (1.2 eq.)propargylamine, 8 mL DCM and 1.08 mL (4 eq.) DIEA are agitated at ATduring 2 h. The DCM is evaporated under reduced pressure and then theresidue is taken over in the ethyl acetate, washed in water (2×) and inbrine (1×). The organic phase is dried on magnesium sulfate and thenevaporated under reduced pressure. The residue is purified bypreparative HPLC to yield 238 mg (78%) of a transparent oil.

LC-MS: t_(R)=2.42 min (method c); m/z: [M−H]⁻=194

CCM: R_(f)=0.14 (AcOEt 2:8 Cyclohexane)

Compound 106:4-(3-(phenylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzenesulfonamide

50 mg (1 eq.) N-(prop-2-ynyl)benzene sulfonamide (105), 87 mg (0.9 eq.)4-iodo-N-(3,3,3-trifluoropropyl)benzene sulfonamide (42), 8.3 mg (0.05eq.) bis(triphenylphosphine) palladium(II) chloride, 40.2 mg (0.9 eq.)copper iodide, and 120 μL (0.5 mL/mmol) triethylamine are placedsuccessively in a schlenk under an argon flow. The anhydrous DMF isadded via a cannula under argon at ambient temperature. The reactionmixture is agitated at 70° C. under argon during 48 h.

The reaction medium is then diluted at AT by adjunction of a mixture ofAcOEt:NH₄Cl_(sat) (1:1). The formed precipitate is filtrated and washedusing ethyl acetate. The organic phase is washed with an aqueoussolution saturated with NH₄Cl (2×) and then in brine (1×), dried onmagnesium sulfate, filtrated on celite and then evaporated under reducedpressure. The solid orange thus obtained is solubilized in the minimumof acetonitrile and then the product is precipitated by adjunction ofdiisoprpylic ether and filtrated to yield 38 mg (33%) of beige powder.

LC-MS: t_(R)=3.13 min (method c); m/z

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.92 (m, 2H, 14+18 or 15+17); 7.74 (d,2H, ³J=8.40 Hz, 5+6); 7.50-7.57 (m, 3H, 16+(14+18 or 15+17)); 7.30 (d,2H, ³J=8.40 Hz, 7+8); 4.07 (s, 2H, 12); 3.08 (t, 2H, ³J=7.10 Hz, 3);2.36 (qt, 2H, ³J₂₋₁=10.60 Hz, ³J₂₋₃=6.80 Hz, 2)

NMR ¹³C (CD₃OD, 75 MHz): δ ppm=142.3 (4); 141.2 (13); 133.7 (16); 133.2(7+8); 130.1 (14+18ou15+17); 128.4 (14+18ou15+17); 128.3 (9); 127.9(5+6); 127.5 (q, ¹J=276.7 Hz, 1); 88.7 (11); 83.3 (10); 37.4 (3); 35.2(q, ²J=28.2 Hz, 2); 33.8 (12)

Compound 107: N-(prop-2-ynyl)methane sulfonamide

A solution of 288 μL (1 eq.) methane sulfonic acid chloride in 3 mLdiethyl ether is added to a solution of 500 μL (2 eq.) propargylamine in6 mL diethyl ether cooled at 0° C. The mixture is agitated during 30min. The formed precipitate is filtrated and washed twice using ether.The filtrate is evaporated under reduced pressure to yield 178 mg (37%)of a white solid.

LC-MS: t_(R)=1.92 min (method c); m/z: [M+H]⁺=134 NMR ¹H (CDCl₃ 300MHz): δ ppm=4.69 (m, 1H, NH); 4.00 (dd, 2H, ³J_(3-NH)=6.20 Hz,⁴J₃₋₁=2.50 Hz, 2); 3.10 (s, 3H, 4); 2.41 (t, 1H, ³J=2.50 Hz, 1)

Compound 108:4-(3-(methylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzenesulfonamide

136 mg (1.2 eq.) tetrabutylammonium acetate, 1 mg (0.002 eq.) PdEnCat³⁰, 142 mg (1 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)benzenesulfonamide (42) and 50 mg (1 eq.) N-(prop-2-ynyl)methane sulfonamide(107) are added to 500 μL DMF. The solution is agitated during 24 h at80° C. A mixture of AcOEt:NH₄Cl_(sat) 1:1 (2 mL) is added to thereaction medium. The mixture is agitated for 10 min and then filtratedto recover the palladium beads. The product is recovered in the organicphase by extraction Water:AcOEt. The organic phase is then washed inbrine (1×), dried on magnesium sulfate, filtrated on celite andevaporated under reduced pressure. The product is purified on apre-packed silica column (Cyclohexane 95:5 Isopropanol→Cyclohexane 90:10Isopropanol). 39 mg (27%) of a beige solid are recovered.

LC-MS: t_(R)=2.78 min (method c); m/z: [M+H]⁺=385

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.84 (d, 2H, ³J=8.59 Hz, 5+6 or 7+8);7.64 (d, 2H, ³J=8.59 Hz, 5+6 or 7+8); 4.17 (s, 2H, 12); 3.12-3.08 (m,5H, 13+3); 2.38 (qt, 2H, ³J₂₋₁=10.78 Hz, ³J₂₋₃=7.28 Hz, 2)

Compound 111: 4-iodo-N-(3,3,3-trifluoropropyl)benzamide

300 mg (1 eq.) 4-acetylbenzoic acid, 181 mg (1 eq.)3,3,3-trifluoropropylamine hydrochloride, 33 mg (0.2 eq.) HOBT, 551 mg(1.1 eq.) HBTU and 10 mL DMF are successively added in a 25 mL flask.840 μL (4 eq.) DIEA are then added and the mixture is agitated 2 h at ATThe DMF is evaporated under reduced pressure. The residue is taken overin the ethyl acetate and then washed in brine (2×). The organic phase isthen evaporated under reduced pressure and the product is then purifiedon a pre-packed silica column (Cyclohexane 8:2 AcOEt) to yield 327 mg(77%) of white powder.

LC-MS: t_(R)=3.25 min (method c); m/z: [M+H]⁺=344

NMR ¹H (CDCl₃ 300 MHz): δ ppm=7.80 (d, 2H, ³J=8.50 Hz); 7.47 (d, ³J=8.50Hz); 6.34 (m, 1H, NH); 3.72 (q, 2H, ³J=6.30 Hz, 3); 2.47 (tq, 2H,³J₂₋₁=10.70 Hz, ³J₂₋₃=6.40 Hz, 2)

NMR ¹⁹F CDCl₃ 282.4 MHz): δ ppm=−64.92 (t, ³J=10.8 Hz)

Compound 112:4-(3-(phenylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzamide

50 mg (1 eq.) N-(prop-2-ynyl)benzene sulfonamide (105), 83.5 mg (0.95eq.) 4-iodo-N-(3,3,3-trifluoropropyl)benzamide (111), 9 mg (0.05 eq.)bis(triphenylphosphine)palladium(II) chloride, 48 mg (1 eq.) copperiodide, and 128 μL (0.5 mL/mmol) triethylamine are placed successivelyin a schlenk under argon flow. 1 mL anhydrous DMF is added via a cannulaunder argon at AT. The reaction mixture is agitated at 70° C. underargon during 48 h. The reaction medium is diluted at AT by adjunction ofa mixture of 1:1 AcOEt:NH₄Cl_(sat). The precipitate thus formed isfiltrated and washed using ethyl acetate. An extraction is performedusing a mixture AcOEt:NH₄Cl_(sat). The organic phase is washed in brine(1×), dried on magnesium sulfate, filtrated on celite and thenevaporated under reduced pressure. The brown oil thus obtained ispurified by pre-packed silica column (DCM 95:5 AcOEt) to yield 30 mg(29%) of a light brown solid.

LC-MS: t_(R)=5.43 min (method d); m/z: [M+H]⁺=411

NMR ¹H (CD₃OD, 300 MHz): δ ppm=7.94 (dd, 2H, ³J=7.40 Hz, ⁴J=1.60 Hz,15+19); 7.71 (d, 2H, ³J=8.40 Hz, 6+7 or 8+9); 7.55 (m, 3H, 16+17+18);7.21 (d, 2H, ³J=8.40 Hz, 6+7 or 8+9); 4.07 (s, 2H, 13); 3.62 (t, 2H,³J=7.00 Hz, 3); 2.52 (qt, 2H, ³J₂₋₁=10.90 Hz, ³J₂₋₃=7.00 Hz, 2);

Evaluation of the Compounds' Activity

TSA Test (Thermal Shift Assay)

The heat denaturation of proteins is a phenomenon that has been studiedfor a long time, by means of many techniques, based notably oncalorimetry (DSC: Differential Scanning calorimetry) or fluorescence(DSF: Differential Scanning Fluorimetry or also Fluorescence ThermalShift Assay).

The Thermal Shift Assay test uses a fluorescent marker, in our caseSypro Orange™. The fluorescence intensity of this compound is amplifiedwhen it is in a hydrophobic environment. Thus, in normal conditions, inan aqueous solution and in the presence of the native protein, themarker fluoresces little, as the hydrophobic zones of the protein arenot accessible. When the protein becomes denatured under the effect ofheat, the marker will be able to interact with its hydrophobic regions,causing an increase in fluorescence. It is thus possible to determinethe melting temperature of the protein, denoted by T_(m), correspondingto a state where the protein is 50% denatured.

This technique enables the stabilizing or destabilizing effect on theprotein of a specific ligand to be measured. For this, the experience iscarried out with the protein alone and then by incubating the proteinwith a potential ligand. Two different values for the meltingtemperature are then obtained that enable a temperature differenceΔT_(m) expressed in ° C. to be defined. If ΔT_(m)>0, the ligandstabilizes the protein, if ΔT_(m)<0, the ligand destabilizes theprotein. The greater |ΔT_(m)|, the greater the ligand's stabilizing ordestabilizing effect. Yet as the stabilizing power is linked to theligand's affinity for the protein, the higher the ΔT_(m) is, the greaterthe ligand's affinity for this protein.

This TSA fluorescence test thus enables the affinity of our ligands forthe EthR protein to be quantified and for them to, be classifiedaccording to their ascending ΔT_(m) value.

Surface Plasmon Resonance test (SPR) (described in the article“Ethionamide Boosters Combining Bioisosteric Replacement andStructure-Based Drug Design to Solve Pharmacokinetic Issues in a seriesof potent 1,2,4-Oxadiazole EthR Inhibitors” published in 2012 in theJournal of Medicinal Chemistry)

After having measured the ligands' affinity for the protein, it isnecessary to verify that this does indeed result in the inactivation ofthe transcriptional repressor, thus preventing it from binding to itsoperon. For this, a functional test based on the principle of surfaceplasmon resonance is used. Surface Plasmon Resonance (SPR) makes itpossible to visualize in real time the phenomena of association ordissociation between a partner immobilized on a biosensor and, a secondpartner injected in a continuous flow onto this surface. In the presentcase, the SPR technique enables the interaction between the EthR protein(analyte injected in continuous flow) and the ethA gene promoter(partner immobilized on the surface) to be visualized. Two cells areused for the test: a measuring cell onto which the so-called relevantDNA is affixed, i.e. corresponding to the ethA gene promoter, and acontrol cell on which is a non-relevant (thus different) DNA strand ofsame length, enabling the non-specific protein/DNA interactions to beremoved. In a first step, the EthR protein is injected alone, untilsaturation, which enables a signal SI_(EthR) corresponding to thequantity of EthR protein that has come to bind to the DNA to bemeasured. In a second step, the experience is reiterated in the presenceof a potential ligand at different concentrations. If the compound bindsto the EthR, thus preventing it from coming to bind on the DNA, adiminution of the response of the dose-dependent signal (SI_(EthR+lig))is observed.

By using the equation hereafter, it is possible to calculate for eachconcentration a percentage for the inhibition of the ligand underexamination:

${\%{Inhibition}} = {100 \times \frac{{SI}_{EthR} - {SI}_{{EthR} + {Lig}}}{{SI}_{EthR}}}$

By representing the variation of the inhibition percentage depending onthe ligand concentration, a value for IC₅₀ can be deduced.

Potentiation of Ethionamid cell test (described in the article“Ethionamide Boosters Combining Bioisosteric Replacement andStructure-Based Drug Design to Solve Pharmacokinetic Issues in a seriesof potent 1,2,4-Oxadiazole EthR Inhibitors” published in 2012 in theJournal of Medicinal Chemistry)

The preceding test validates the, compounds' capacity to inhibit theEethR/DNA interaction by binding to the EthR protein. The third testused makes it possible to ascertain that these compounds are capable ofpotentiating the bactericide activity of ethionamide on M. tuberculosisalone or on macrophages infected by M. tuberculosis. This test is a“High Content Screening” (HCS) or dense content screening test. HCStests are performed on cell cultures that enable certain phenotypicfeatures of a microorganism (e.g. a bacterium) in a given environment tobe studied. The phenotypic changes observed can range from the increase(or decrease) of the production of certain marked proteins to themodification of the morphology of the microorganism under consideration.

This test aims to determine the ligand concentration necessary topotentiate ten times the activity of ethionamide (ETH).

To measure, the ligand concentration necessary for potentiating tentimes the activity of ETH, a constant concentration of ethionamide (0.1μg/mL corresponding to 1/10^(th) of its CMI₉₉) is chosen. By varying theligand concentration, the concentration necessary to inhibit 50% of thebacterial growth, i.e. the concentration necessary to potentiate tentimes the activity of ethionamide, can be determined. This concentrationwill be denoted EC₅₀.

Measurement of the Solubility

40 μL of a solution at 10 mM in DMSO of the sample are added at 1.96 mLMeOH or PBS at pH 7.4. The samples are then agitated during 24 h at AT,centrifuged during 5 min and then filtrated on filters of 0.45 μm size.20 μL of each solution are then added to 180 μL MeOH and then analyzedby LC-MS. The solubility is determined as ratio of the surfaces of themass signals PBS/MeOH.

Measurement of the log D

40 μL of a solution at 10 mM in the DMSO of the sample are added to 1.96mL of a mixture of 1/1 octanol/PBS at pH 7.4. The solution is agitatedduring 2 h at AT. 20 μL of each phase are added to 180 μL MeOH andanalyzed by LC-MS. Each compound is evaluated in triplicate. The log Dis determined as being the logarithm of the ratio of the productconcentrations in the octanol and PBS phases, determined par the masssignals.

Measured Biological Activities

Each of the following tables consolidates the formulas of the testedcompounds or the definitions of the different variable radicalsmentioned in the Markush formula preceding the respective table andcorresponding to the tested compounds as well as the values of ΔT_(m),EC₅₀ experimentally measured according to the aforementioned protocolsand which corresponds to the number of atoms constituting each moleculeand different from the hydrogen atom.

TABLE 1 Compound R2 ΔT_(m) (° C.) EC₅₀ (μM) HA 6 H₃C→ 6.1 5.7 21 17

5.3 7.9 23 21

4.6 5.0 24

TABLE 2 Compound R1 n ΔT_(m) (° C.) EC₅₀ (μM) HA 6 —CH(CH₃)₂ 2 6.1 5.721 23 —C(CH₃)₃ 2 2.3 >20 22 24 —CF₃ 2 8.5 0.29 22 25 —CF₂CF₃ 1 8.6 >2024 26 —CF₃ 1 6.3 7.9 21 27 —CF₃ 3 6.6 >2.5 23 28 —CF₂CF₂CF₃ 1 7.3 >2.527

TABLE 3 Compound R3 ΔT_(m) (° C.) EC₅₀ (μM) HA 24 H₃C→ 8.5 0.29 22 33

9.5 0.86 26 34

0.15 0.15 27 35

11.6 0.30 28 36

— 0.21 28 38

12.4 0.39 27 39

7.3 0.20 29

TABLE 4 Compound Structure ΔT_(m) (° C.) EC₅₀ (μM) HA 41

6.8 0.66 22 42

— 0.30 25

TABLE 5 Compound R3 ΔT_(m) (° C.) EC₅₀ (μM) HA 43 H3C— 11.4 0.083 21 52

10.1 0.19 26 53

13.2 0.33 27 50

9.6 0.041 28 103

6.6 0.32 28 104

1.2 0.15 31 47

13.0 0.030 26 54

9.6 >2.5 25 55

8.2 0.73 26 49

12.6 <0.040 24 56 H 8.1 0.36 20 57

12.6 <0.010 26 58

13.3 <0.010 28

TABLE 6 Compound R2 ΔT_(m) (° C.) EC₅₀ (μM) HA 62 F — 0.055 22 64 Cl 8.70.35 22

TABLE 7 Compound Ar EC₅₀ (μM) HA 67

0.120 21 71

1.7 21

TABLE 8 Com- ΔT_(m) EC₅₀ pound Structure (° C.) (μM) HA 92

6.0 1.1 18

TABLE 9 Compound R3 ΔT_(m) (° C.) EC₅₀ (μM) HA 93

3.8 >10 25 94

4.1 1.2 24 95

3.5 1.7 23 97

1.2 2.0 23

TABLE 10 Compound R3 Het EC₅₀ (μM) HA 72 H₃C→

0.18 21 75 H₃C→

0.062 21 78 H₃C→

0.21 21 80 H₃C→

0.96 21 83 H₃C→

1.4 21 90

0.13 22

TABLE 11 Com- ΔT_(m,) EC₅₀ pound R3 T (° C.) (μM) HA 106

SO₂ 3.3 1.8 29 108

SO₂ 1.4 >10 24 112

CO 4.2 0.23 28

TABLE 12 Compound IC₅₀ (μM) Solubilité (μM) LogD 6 4.9 ± 0.1 20 3.55 240.55 ± 0.02 41.4 3.12 35 — 2.8 3.76 38 — <1 >4 43 0.48 ± 0.06 46.9 2.8249 0.44 ± 0.01 4.4 3.91 57 — 29 3.07 58 — 3.3 3.95

The invention claimed is:
 1. A compound of formula (II):

in which Y and Z are CH; T is chosen from CO or SO₂; n is an integergreater than or equal to 1 and lower than or equal to 3; R is R-7:

in which: R2 is chosen from H, F, Cl, Br, I; R3 is a group chosen fromH, linear or branched C1-C6 alkyl chains, linear or branched C1-C6 alkylchains substituted by at least one fluorine atom, C3-C6 cyclic groups,the cyanomethyl group, the azidomethyl group, linear or branched C1-C4alkoxy chains, C-C4 hydroxyalkyl groups, C1-C4 alkyl methyl estergroups, C1-C4 methylcarbonylamino alkyl groups, C1-C4 methylsulfonealkyl groups, the unsubstituted phenyl group, a phenyl group substitutedby one, two or three substituents chosen, independently from oneanother, from C1-C3 alkyl chains, trifluoromethyl, C1-3 alkoxy chains,or by a group chosen among the following groups (II-a and II-b):

in which R4 is a group chosen from H, linear or branched C1-C4 alkylchains, the phenyl group, a phenyl group substituted by at least onehalogen atom, a phenyl group substituted by a linear or branched C1-C4alkyl chain, a phenyl group substituted by a linear or branched C1-C4alkoxy chain and a phenyl group substituted by a trifluoromethyl group.2. The compound according to claim 1, wherein T is CO and R3 is—CH₂SO₂R′ wherein the radical R′ is tert-butyl, methyl, isobutyl,isopentyl, or isohexyl.
 3. The compound according to claim 1, whereinsaid compound corresponds to formula (IV):

in which n, T and R3 are as defined in claim
 1. 4. The compoundaccording to claim 3, wherein T is CO and R3 is —CH₂SO₂R′ wherein theradical R′ is tert-butyl, methyl, isobutyl, isopentyl, or isohexyl. 5.The compound according to claim 1 chosen from the following compounds:Compound 24: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoropropyl)benzenesulfonamide Compound 26:4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoroethyl)benzene sulfonamideCompound 27: 4-(2-methylthiazol-4-yl)-N-(4,4,4-trifluorobutyl)benzenesulfonamide Compound 32:4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide Compound 33:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)methylacetate Compound 34:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)ethylacetate Compound 35:2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)isopropylacetate Compound 36:N-isopropyl-2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)acetamideCompound 38:4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide Compound 39:4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide Compound 43:4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 47:4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamideCompound 49:4-(2-isobutylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound50:4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamideCompound 51: 4 -(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 52:2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)ethylacetate Compound 53:2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)isopropylacetate Compound 54:4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-ethyl carboxylateCompound 55:4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-isopropylcarboxylate Compound 56:4-(thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 62:4-(5-fluoro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamideCompound 64:4-(5-chloro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamideCompound 103:4-(2-(propylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide;and Compound 104:4-(2-(phenylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzamide.6. A method of treatment of bacterial and mycobacterial infectioncomprising administering, to a patient in need thereof, an effectiveamount of a compound according to claim
 1. 7. A method of treatment oftuberculosis, leprosy or atypical mycobacterial infection comprisingadministering, to a patient in need thereof, an effective amount of acompound of claim
 1. 8. A method of treatment of bacterial andmycobacterial infection comprising administering, to a patient in needthereof, an effective amount of a compound according to claim
 3. 9. Amethod of treatment of tuberculosis, leprosy or atypical mycobacterialinfection comprising administering, to a patient in need thereof, aneffective amount of a compound of claim 3.